Drug delivery polymers and uses thereof

ABSTRACT

Described herein are platinum-based brush-arm star polymers (Pt-BASPs), or a pharmaceutical composition thereof, for delivery of platinum-based agents, such as oxaliplatin. Also provided are methods and kits involving the Pt-BASPs, or a pharmaceutical composition thereof, for treating proliferative diseases such as cancers (e.g., lung cancer, head-and-neck cancer, esophagus cancer, stomach cancer, breast cancer, pancreas cancer, colorectal cancer, liver cancer, kidney cancer, or prostate cancer) in a subject.

RELATED APPLICATION

The present application claims priority under 35 U.S.C. § 119(e) to U.S.provisional application, U.S. Ser. No. 62/346,923, filed Jun. 7, 2016,which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to polymers and macromolecules for the deliveryof therapeutic agents and methods of treating diseases.

BACKGROUND OF THE INVENTION

Platinum-based therapeutics form a cornerstone of treatment for solidtumor malignancies. Cisplatin is one of the most effectivechemotherapeutic agents against many forms of cancer includingtesticular cancer, bladder cancer, head and neck cancers, ovariancancer, breast cancer, lung cancer, prostate cancer, and refractorynon-Hodgkin's lymphomas (Jamieson et al., Chem Rev., 1999,99:2467-2498). Despite the extensive use of cisplatin in oncology, thisdrug is associated with significant dose-limiting toxicities includingnephrotoxicity and neurotoxicity (Dhar et al., Proc. Nat. Acad. Sci.,2011, 1850-1855). Significant efforts have been devoted to developingnew strategies for safer and more effective platinum-based therapeutics.

Targeting controlled release polymer systems (e.g., targeted to aparticular tissue or cell type or targeted to a specific diseased tissuebut not normal tissue) is desirable because it reduces the amount of adrug present in tissues of the body that are not targeted (e.g., healthytissue). This is particularly important when treating cancer where it isdesirable that a cytotoxic dose of the drug be delivered to cancer cellswithout killing the surrounding non-cancerous tissue. Effective drugtargeting can reduce the undesirable and sometimes life threatening sideeffects common with many anti-cancer therapies. Controlled releasepolymer systems can be designed to provide a drug level in the optimumrange over a longer period of time, thus increasing the efficacy of thedrug and minimizing problems with patient compliance.

SUMMARY OF THE INVENTION

Platinum-based agents play an important role in the treatment of cancer.Significant adverse reactions related to platinum-based agentsfrequently hinders the use of higher doses to achieve their maximumantineoplastic effects. International Application No. PCT/US2014/033554filed Apr. 9, 2014, describes cisplatin-based brush-arm star polymers(BASPs) using “brush-first” ring-opening metathesis polymerization(ROMP). The present invention provides oxaliplatin or a derivativethereof-based BASPs and their use in the delivery and controlled releaseof oxliplatin. In certain embodiments, the BASPs can be loaded withoxaliplatin or a derivative thereof and one or more therapeutic,diagnostic, or prophylactic agents for multi-agent delivery. In certainembodiments, the BASPs can be loaded with a bis-norbornene oxaliplatinderivative (e.g., oxPt-XL), irinotecan (IRT), and 5-fluorouracil (5FU).

In one aspect, the present invention provides platinum complexes ofFormula (I):

and salts thereof. In certain embodiments, the platinum complexes ofFormula (I), and salts thereof, are prodrugs of a oxaliplatin-basedtherapeutic agent. In certain embodiments, the platinum complexes ofFormula (I), and salts thereof, are used as crosslinkers to preparePt-BASPs for the delivery of oxaliplatin. In certain embodiments, anoxaliplatin-based platinum complex crosslinker is incorporated in BASPs.In certain embodiments, an oxaliplatin-based platinum complexcrosslinker and a macromonomer containing a therapeutic agent areincorporated in the Pt-BASPs (see FIG. 1).

In another aspect, the present invention provides methods of preparingplatinum complexes of Formula (I) and salts thereof. In certainembodiments, the platinum therapeutic agent (e.g., oxaliplatin or aderivative thereof) is oxidized with an oxidant such as hydrogenperoxide, followed by treatment with a norbornene anhydride derivative.

In another aspect, the present invention provides platinum-basedbrush-arm star polymers (Pt-BASP) using “brush-first” ring-openingmetathesis polymerization (ROMP). In certain embodiments, the Pt-BASPdescribed herein can be prepared by (a) reacting a macromonomer ofFormula (III′) (e.g., Formula (III)) with a metathesis catalyst to forma polymerization mixture; and (b) contacting the polymerization mixturefrom step (a) with a platinum complex of Formula (I) (e.g., a solutionof a platinum complex of Formula (I)). In certain embodiments, thepolymer is a brush-arm star polymer (BASP) with the covalently boundplatinum-based agent as the core and poly(ethylene glycol) (PEG) as thecoronas. In certain embodiments, the macromonomer can introduce one ormore therapeutic, diagnostic, or prophylactic agents in addition to theplatinum-based agent (e.g., oxaliplatin or a derivative thereof). Incertain embodiments, the delivery of an agent (including aplatinum-based agent such as oxaliplatin or a derivative thereof)included in a Pt-BASP described herein is ratiometric. In certainembodiments, the delivery of each agent included in a Pt-BASP describedherein is ratiometric. In certain embodiments, the release of two ormore agents (including oxaliplatin or a derivative thereof) included ina Pt-BASP described herein from the Pt-BASP is orthogonal. In certainembodiments, the delivery of two or more agents (including oxaliplatinor a derivative thereof) included in a Pt-BASP described herein isorthogonal. In certain embodiments, the macromonomer introduces one ormore anti-cancer agents for combination delivery. In certainembodiments, the provided Pt-BASPs are loaded with more than onetherapeutic, diagnostic, or prophylactic agents and can be prepared by(a) reacting a macromonomer of Formula (III′) (e.g., Formula (III))having one therapeutic, diagnostic, or prophylactic agent, with anothermacromonomer of Formula (III′) (e.g., Formula (III)) having a differenttherapeutic, diagnostic, or prophylactic agent, in the presence of ametathesis catalyst to form a polymerization mixture; and (b) contactingthe polymerization mixture from step (a) with a platinum complex ofFormula (I) (e.g., a solution of a platinum complex of Formula (I)). Incertain embodiments, the Pt-BASPs as described herein are loaded withoxaliplatin or a derivative thereof, IRT, and 5FU. In certainembodiments, the Pt-BASPs as described herein are loaded withoxaliplatin or a derivative thereof, SN-38, and 5FU.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a polymer described herein and apharmaceutically acceptable excipient. In certain embodiments, a polymerdescribed herein is provided as a polymeric nanoparticle. The size ofthe polymeric nanoparticle may be determined by the molar ratio of allthe macromonomers to the crosslinker employed in a method of preparingthe polymeric nanoparticle (e.g., Method A′ or B′, such as Method A orB). In certain embodiments, the polymeric nanoparticle is of radius sizeof about 1 nm to about 1000 nm. In certain embodiments, the polymericnanoparticle is of radius size of about 1 nm to about 200 nm. In certainembodiments, the polymeric nanoparticle is of radius size of about 1 nmto about 20 nm. In certain embodiments, the polymeric nanoparticle is ofradius size of about 1 nm to about 10 nm. In certain embodiments, thepharmaceutical compositions described herein include a therapeuticallyeffective amount of a polymer described herein. The pharmaceuticalcomposition may be useful for treating a proliferative disease such ascancer.

In another aspect, the present invention provides methods for treatingproliferative diseases. Exemplary proliferative diseases include cancers(e.g., leukemia, melanoma, multiple myeloma, solid tumors), benignneoplasms, angiogenesis, angiogenesis-associated diseases, inflammatorydiseases, autoinflammatory diseases, and autoimmune diseases. In certainembodiments, the cancer is colorectal cancer. In certain embodiments,the cancer is pancreatic cancer. In certain embodiments, the cancer ismetastatic pancreatic cancer.

In another aspect, the present invention provides kits comprising aplatinum complex of Formula (I) and/or a polymer described herein. Thekits of the invention may include a single dose or multiple doses of aplatinum complex of Formula (I) and/or a polymer described herein. Theprovided kits may be useful for the treatment of proliferative diseasessuch as cancers. In certain embodiments, the kits described hereinfurther include instructions for administering the platinum complex ofFormula (I) and/or a polymer described herein. The kits may also includepackaging information describing the use or prescribing information forthe subject or a health care professional. Such information may berequired by a regulatory agency such as the U.S. Food and DrugAdministration (FDA). The kit may also optionally include a device foradministration of the compound or composition, for example, a syringefor parenteral administration.

The details of certain embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, Figures, Examples, and Claims.

Definitions Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The invention additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

In a formula,

is a single bond where the stereochemistry of the moieties immediatelyattached thereto is not specified, --- is absent or a single bond, and

or

is a single or double bond.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of ¹²C with ¹³Cor ¹⁴C are within the scope of the disclosure. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” refers to heteroalkyl,heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., —CF₃, Bn).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkylmoiety has 1 to 8 carbon atoms (“C₁₋₈ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁₋₄haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbonatoms (“C₁₋₃ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). Examples of haloalkyl groupsinclude —CHF₂, —CH₂F, —CF₃, —CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂,—CF₂C₁, and the like.

The term “heteroalkyl” refers to an alkyl group which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry

is not specified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently unsubstituted (an “unsubstitutedalkynyl”) or substituted (a “substituted alkynyl”) with one or moresubstituents. In certain embodiments, the alkynyl group is anunsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynyl groupis a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 3 heteroatoms include, withoutlimitation, triazinanyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyl,and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 π electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by an aryl group, wherein the point of attachment is on thealkyl moiety.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14 π electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by a heteroaryl group, wherein the point of attachment is onthe alkyl moiety.

The term “unsaturated bond” refers to a double or triple bond.

The term “unsaturated” or “partially unsaturated” refers to a moietythat includes at least one double or triple bond.

The term “saturated” refers to a moiety that does not contain a doubleor triple bond, i.e., the moiety only contains single bonds.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, cycloalkyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl groups are optionally substituted. “Optionallysubstituted” refers to a group which may be substituted or unsubstituted(e.g., “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or“unsubstituted” heteroalkenyl, “substituted” or “unsubstituted”heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, and includes any of thesubstituents described herein that results in the formation of a stablecompound. The present invention contemplates any and all suchcombinations in order to arrive at a stable compound. For purposes ofthis invention, heteroatoms such as nitrogen may have hydrogensubstituents and/or any suitable substituent as described herein whichsatisfy the valencies of the heteroatoms and results in the formation ofa stable moiety. The invention is not intended to be limited in anymanner by the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃⁺X⁻, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(aa)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups; each instance of R^(bb) is, independently, selected fromhydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(bb)groups are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd)groups; wherein X⁻ is a counterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂R^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)(OR^(ee))₂,—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups, or two geminalR^(dd) substituents can be joined to form ═O or ═S; wherein X⁻ is acounterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃-10 carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃ —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂, —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa),—OSO₂R^(aa), —OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻,—OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂,and —OP(═O)(N(R^(bb)))₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are asdefined herein.

The term “thiol” or “thio” refers to the group —SH. The term“substituted thiol” or “substituted thio,” by extension, refers to athiol group wherein the sulfur atom directly attached to the parentmolecule is substituted with a group other than hydrogen, and includesgroups selected from —SR^(aa), —S═SR^(cc), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —SC(═O)OR^(aa), and —SC(═O)R^(aa), wherein R^(aa) andR^(cc) are as defined herein.

The term “amino” refers to the group —NH₂. The term “substituted amino,”by extension, refers to a monosubstituted amino, a disubstituted amino,or a trisubstituted amino. In certain embodiments, the “substitutedamino” is a monosubstituted amino or a disubstituted amino group.

The term “sulfonyl” refers to a group selected from —SO₂N(R^(bb))₂,—SO₂R^(aa), and —SO₂OR^(aa), wherein R^(aa) and R^(bb) are as definedherein.

The term “sulfinyl” refers to the group —S(═O)R^(aa), wherein R^(aa) isas defined herein.

The term “acyl” refers to a group having the general formula—C(═O)R^(X1), —C(═O)OR^(X1), —C(═O)—O—C(═O)R^(X1), —C(═O)SR^(X1),—C(═O)N(R^(X1))₂, —C(═S)R^(X1), —C(═S)N(R^(X1))₂, and —C(═S)S(R^(X1)),—C(═NR^(X1))R^(X1), —C(═NR^(X1))OR^(X1), —C(═NR^(X1))SR^(X1), and—C(═NR^(X1))N(R^(X1))₂, wherein R^(X1) is hydrogen; halogen; substitutedor unsubstituted hydroxyl; substituted or unsubstituted thiol;substituted or unsubstituted amino; substituted or unsubstituted acyl,cyclic or acyclic, substituted or unsubstituted, branched or unbranchedaliphatic; cyclic or acyclic, substituted or unsubstituted, branched orunbranched heteroaliphatic; cyclic or acyclic, substituted orunsubstituted, branched or unbranched alkyl; cyclic or acyclic,substituted or unsubstituted, branched or unbranched alkenyl;substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- ordi-heteroaliphaticamino, mono- or di-alkylamino, mono- ordi-heteroalkylamino, mono- or di-arylamino, or mono- ordi-heteroarylamino; or two R^(X1) groups taken together form a 5- to6-membered heterocyclic ring. Exemplary acyl groups include aldehydes(—CHO), carboxylic acids (—CO₂H), ketones, acyl halides, esters, amides,imines, carbonates, carbamates, and ureas. Acyl substituents include,but are not limited to, any of the substituents described herein, thatresult in the formation of a stable moiety (e.g., aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl,thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino,heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl,aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like,each of which may or may not be further substituted).

The term “carbonyl” refers a group wherein the carbon directly attachedto the parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), and imines(—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(aa) and R^(bb) are as defined herein.

The term “silyl” refers to the group —Si(R^(aa))₃, wherein R^(aa) is asdefined herein.

The term “oxo” refers to the group ═O, and the term “thiooxo” refers tothe group ═S.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR, —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(aa),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀heteroalkyl, C₂₋₁₀ heteroalkenyl, C₂₋₁₀ heteroalkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, o-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts).

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb)) 2)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

The term “heteroatom” refers to an atom that is not hydrogen or carbon.In certain embodiments, the heteroatom is nitrogen. In certainembodiments, the heteroatom is oxygen. In certain embodiments, theheteroatom is sulfur.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻, AsF₆ ⁻, SbF₆⁻, B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, andcarborane anions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplarycounterions which may be multivalent include CO₃ ²⁻, HPO₄ ²⁻, PO₄ ³⁻,B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃ ²⁻, carboxylate anions (e.g., tartrate, citrate,fumarate, maleate, malate, malonate, gluconate, succinate, glutarate,adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates,aspartate, glutamate, and the like), and carboranes.

A “hydrocarbon chain” refers to a substituted or unsubstituted divalentalkyl, alkenyl, or alkynyl group. A hydrocarbon chain includes (1) oneor more chains of carbon atoms immediately between the two radicals ofthe hydrocarbon chain; (2) optionally one or more hydrogen atoms on thechain(s) of carbon atoms; and (3) optionally one or more substituents(“non-chain substituents,” which are not hydrogen) on the chain(s) ofcarbon atoms. A chain of carbon atoms consists of consecutivelyconnected carbon atoms (“chain atoms”) and does not include hydrogenatoms or heteroatoms. However, a non-chain substituent of a hydrocarbonchain may include any atoms, including hydrogen atoms, carbon atoms, andheteroatoms. For example, hydrocarbon chain —C^(A)H(C^(B)H₂CCH₃)—includes one chain atom C^(A), one hydrogen atom on C^(A), and non-chainsubstituent —(C^(B)H₂CCH₃). The term “C_(x) hydrocarbon chain,” whereinx is a positive integer, refers to a hydrocarbon chain that includes xnumber of chain atom(s) between the two radicals of the hydrocarbonchain. If there is more than one possible value of x, the smallestpossible value of x is used for the definition of the hydrocarbon chain.For example, —CH(C₂H₅)— is a C₁ hydrocarbon chain, and

is a C₃ hydrocarbon chain. When a range of values is used, the meaningof the range is as described herein. For example, a C₃₋₁₀ hydrocarbonchain refers to a hydrocarbon chain where the number of chain atoms ofthe shortest chain of carbon atoms immediately between the two radicalsof the hydrocarbon chain is 3, 4, 5, 6, 7, 8, 9, or 10. A hydrocarbonchain may be saturated (e.g., —(CH₂)₄—). A hydrocarbon chain may also beunsaturated and include one or more C═C and/or C≡C bonds anywhere in thehydrocarbon chain. For instance, —CH═CH—(CH₂)₂—, —CH₂—C≡C—CH₂—, and—C≡C—CH═CH— are all examples of a unsubstituted and unsaturatedhydrocarbon chain. In certain embodiments, the hydrocarbon chain isunsubstituted (e.g., —C≡C— or —(CH₂)₄—). In certain embodiments, thehydrocarbon chain is substituted (e.g., —CH(C₂H₅)— and —CF₂—). Any twosubstituents on the hydrocarbon chain may be joined to form anoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl ring.For instance,

are all examples of a hydrocarbon chain. In contrast, in certainembodiments,

are not within the scope of the hydrocarbon chains described herein.When a chain atom of a C_(x) hydrocarbon chain is replaced with aheteroatom, the resulting group is referred to as a C_(x) hydrocarbonchain wherein a chain atom is replaced with a heteroatom, as opposed toa C_(x-1) hydrocarbon chain. For example,

is a C₃ hydrocarbon chain wherein one chain atom is replaced with anoxygen atom.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

The use of the phrase “at least one instance” refers to 1, 2, 3, 4, ormore instances, but also encompasses a range, e.g., for example, from 1to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4instances, inclusive.

The term “derivative” of a compound refers to a compound derived fromthis compound by one or more chemical or physical transformations. Incertain embodiments, a derivative of a compound is a salt, solvate,hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopicallylabeled derivatives or a prodrug of a compound. In certain embodiments,a derivative of a compound is compound from one or more steps of organictransformations. Exemplary organic transformations include, but are notlimited to oxidation, reduction, halogenation, esterification,epoxidation, hydrolysis, deprotonation, etc.

The term “small molecule” refers to molecules, whethernaturally-occurring or artificially created (e.g., via chemicalsynthesis) that have a relatively low molecular weight. Typically, asmall molecule is an organic compound (i.e., it contains carbon). Thesmall molecule may contain multiple carbon-carbon bonds, stereocenters,and other functional groups (e.g., amines, hydroxyl, carbonyls, andheterocyclic rings, etc.). In certain embodiments, the molecular weightof a small molecule is not more than 2,000 g/mol. In certainembodiments, the molecular weight of a small molecule is not more than1,500 g/mol. In certain embodiments, the molecular weight of a smallmolecule is not more than 1,000 g/mol, not more than 900 g/mol, not morethan 800 g/mol, not more than 700 g/mol, not more than 600 g/mol, notmore than 500 g/mol, not more than 400 g/mol, not more than 300 g/mol,not more than 200 g/mol, or not more than 100 g/mol. In certainembodiments, the molecular weight of a small molecule is at least 100g/mol, at least 200 g/mol, at least 300 g/mol, at least 400 g/mol, atleast 500 g/mol, at least 600 g/mol, at least 700 g/mol, at least 800g/mol, or at least 900 g/mol, or at least 1,000 g/mol. Combinations ofthe above ranges (e.g., at least 200 g/mol and not more than 500 g/mol)are also possible. In certain embodiments, the small molecule is atherapeutically active agent, such as a drug (e.g., a molecule approvedby the U.S. Food and Drug Administration as provided in the Code ofFederal Regulations (C.F.R.)). The small molecule may also be complexedwith one or more metal atoms and/or metal ions. In this instance, thesmall molecule is also referred to as a “small organometallic molecule.”Preferred small molecules are biologically active in that they produce abiological effect in animals, preferably mammals, more preferablyhumans. Small molecules include radionuclides and imaging agents. Incertain embodiments, the small molecule is a drug. Preferably, thoughnot necessarily, the drug is one that has already been deemed safe andeffective for use in humans or animals by the appropriate governmentalagency or regulatory body. For example, drugs approved for human use arelisted by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440through 460, incorporated herein by reference; drugs for veterinary useare listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporatedherein by reference. All listed drugs are considered acceptable for usein accordance with the present invention.

The term “polymer” refers to a compound comprising eleven or morecovalently connected repeating units. In certain embodiments, a polymeris naturally occurring. In certain embodiments, a polymer is synthetic(e.g., not naturally occurring). In certain embodiments, the M_(w) of apolymer is between 1,000 and 2,000, between 2,000 and 10,000, between10,000 and 30,000, between 30,000 and 100,000, between 100,000 and300,000, between 300,000 and 1,000,000, g/mol, inclusive. In certainembodiments, the M_(w) of a polymer is between 2,000 and 1,000,000,g/mol, inclusive.

A “protein,” “peptide,” or “polypeptide” comprises a polymer of aminoacid residues linked together by peptide bonds. The term refers toproteins, polypeptides, and peptides of any size, structure, orfunction. Typically, a protein will be at least three amino acids long.A protein may refer to an individual protein or a collection ofproteins. Inventive proteins preferably contain only natural aminoacids, although non natural amino acids (i.e., compounds that do notoccur in nature but that can be incorporated into a polypeptide chain)and/or amino acid analogs as are known in the art may alternatively beemployed. One or more of the amino acids in a protein may be protected.Also, one or more of the amino acids in a protein may be modified, forexample, by the addition of a chemical entity such as a carbohydrategroup, a hydroxyl group, a phosphate group, a farnesyl group, anisofarnesyl group, a fatty acid group, a linker for conjugation orfunctionalization, or other modification. A protein may also be a singlemolecule or may be a multi-molecular complex. A protein may be afragment of a naturally occurring protein or peptide. A protein may benaturally occurring, recombinant, synthetic, or any combination ofthese. In certain embodiments, a protein comprises between 2 and 10,between 10 and 30, between 30 and 100, between 100 and 300, or between300 and 1,000, inclusive, amino acids. In certain embodiments, the aminoacids in a protein are natural amino acids. In certain embodiments, theamino acids in a protein are unnatural amino acids. In certainembodiments, the amino acids in a protein are a combination of naturalamino acids and unnatural amino acids.

The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid”,“nucleic acid molecule”, “nucleic acid sequence”, and “oligonucleotide”refer to a series of nucleotide bases (also called “nucleotides”) in DNAand RNA, and mean any chain of two or more nucleotides. Thepolynucleotides can be chimeric mixtures or derivatives or modifiedversions thereof, single-stranded or double-stranded. Theoligonucleotide can be modified at the base moiety, sugar moiety, orphosphate backbone, for example, to improve stability of the molecule,its hybridization parameters, etc. The antisense oligonuculeotide maycomprise a modified base moiety which is selected from the groupincluding 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)uracil, 5-carboxymethylaminomethyl-2-thiouridine,5-carboxymethylaminomethyluracil, dihydrouracil,beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine,2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine,7-methylguanine, 5-methylaminomethyluracil,5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,5′-methoxycarboxymethyluracil, 5-methoxyuracil,2-methylthio-N6-isopentenyladenine, wybutoxosine, pseudouracil,queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil,4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester,uracil-5-oxyacetic acid, 5-methyl-2-thiouracil,3-(3-amino-3-N-2-carboxypropyl) uracil, a thio-guanine, and2,6-diaminopurine. A nucleotide sequence typically carries geneticinformation, including the information used by cellular machinery tomake proteins and enzymes. These terms include double- orsingle-stranded genomic and cDNA, RNA, any synthetic and geneticallymanipulated polynucleotide, and both sense and antisensepolynucleotides. This includes single- and double-stranded molecules,i.e., DNA-DNA, DNA-RNA and RNA-RNA hybrids, as well as “protein nucleicacids” (PNAs) formed by conjugating bases to an amino acid backbone.This also includes nucleic acids containing carbohydrate or lipids.Exemplary DNAs include single-stranded DNA (ssDNA), double-stranded DNA(dsDNA), plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA(cDNA), antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatelliteDNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA),provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA.Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded RNA(dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA), precursormessenger RNA (pre-mRNA), small hairpin RNA or short hairpin RNA(shRNA), microRNA (miRNA), guide RNA (gRNA), transfer RNA (tRNA),antisense RNA (asRNA), heterogeneous nuclear RNA (hnRNA), coding RNA,non-coding RNA (ncRNA), long non-coding RNA (long ncRNA or lncRNA),satellite RNA, viral satellite RNA, signal recognition particle RNA,small cytoplasmic RNA, small nuclear RNA (snRNA), ribosomal RNA (rRNA),Piwi-interacting RNA (piRNA), polyinosinic acid, ribozyme, flexizyme,small nucleolar RNA (snoRNA), spliced leader RNA, viral RNA, and viralsatellite RNA.

Polynucleotides described herein may be synthesized by standard methodsknown in the art, e.g., by use of an automated DNA synthesizer (such asthose that are commercially available from Biosearch, AppliedBiosystems, etc.). As examples, phosphorothioate oligonucleotides may besynthesized by the method of Stein et al., Nucl. Acids Res., 16, 3209,(1988), methylphosphonate oligonucleotides can be prepared by use ofcontrolled pore glass polymer supports (Sarin et al., Proc. Natl. Acad.Sci. U.S.A. 85, 7448-7451, (1988)). A number of methods have beendeveloped for delivering antisense DNA or RNA to cells, e.g., antisensemolecules can be injected directly into the tissue site, or modifiedantisense molecules, designed to target the desired cells (antisenselinked to peptides or antibodies that specifically bind receptors orantigens expressed on the target cell surface) can be administeredsystemically. Alternatively, RNA molecules may be generated by in vitroand in vivo transcription of DNA sequences encoding the antisense RNAmolecule. Such DNA sequences may be incorporated into a wide variety ofvectors that incorporate suitable RNA polymerase promoters such as theT7 or SP6 polymerase promoters. Alternatively, antisense cDNA constructsthat synthesize antisense RNA constitutively or inducibly, depending onthe promoter used, can be introduced stably into cell lines. However, itis often difficult to achieve intracellular concentrations of theantisense sufficient to suppress translation of endogenous mRNAs.Therefore a preferred approach utilizes a recombinant DNA construct inwhich the antisense oligonucleotide is placed under the control of astrong promoter. The use of such a construct to transfect target cellsin the patient will result in the transcription of sufficient amounts ofsingle stranded RNAs that will form complementary base pairs with theendogenous target gene transcripts and thereby prevent translation ofthe target gene mRNA. For example, a vector can be introduced in vivosuch that it is taken up by a cell and directs the transcription of anantisense RNA. Such a vector can remain episomal or become chromosomallyintegrated, as long as it can be transcribed to produce the desiredantisense RNA. Such vectors can be constructed by recombinant DNAtechnology methods standard in the art. Vectors can be plasmid, viral,or others known in the art, used for replication and expression inmammalian cells. Expression of the sequence encoding the antisense RNAcan be by any promoter known in the art to act in mammalian, preferablyhuman, cells. Such promoters can be inducible or constitutive. Any typeof plasmid, cosmid, yeast artificial chromosome, or viral vector can beused to prepare the recombinant DNA construct that can be introduceddirectly into the tissue site.

The polynucleotides may be flanked by natural regulatory (expressioncontrol) sequences or may be associated with heterologous sequences,including promoters, internal ribosome entry sites (IRES) and otherribosome binding site sequences, enhancers, response elements,suppressors, signal sequences, polyadenylation sequences, introns, 5′-and 3′-non-coding regions, and the like. The nucleic acids may also bemodified by many means known in the art. Examples of such modificationsinclude methylation, “caps”, substitution of one or more of thenaturally occurring nucleotides with an analog, and internucleotidemodifications, such as, for example, those with uncharged linkages(e.g., methyl phosphonates, phosphotriesters, phosphoroamidates,carbamates, etc.) and with charged linkages (e.g., phosphorothioates,phosphorodithioates, etc.). Polynucleotides may contain one or moreadditional covalently linked moieties, such as, for example, proteins(e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine,etc.), intercalators (e.g., acridine, psoralen, etc.), chelators (e.g.,metals, radioactive metals, iron, oxidative metals, etc.), andalkylators. The polynucleotides may be derivatized by formation of amethyl or ethyl phosphotriester or an alkyl phosphoramidate linkage.Furthermore, the polynucleotides herein may also be modified with alabel capable of providing a detectable signal, either directly orindirectly. Exemplary labels include radioisotopes, fluorescentmolecules, isotopes (e.g., radioactive isotopes), biotin, and the like.

The term “salt” refers to ionic compounds that result from theneutralization reaction of an acid and a base. A salt is composed of oneor more cations (positively charged ions) and one or more anions(negative ions) so that the salt is electrically neutral (without a netcharge). Salts of the compounds of this invention include those derivedfrom inorganic and organic acids and bases. Examples of acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, andperchloric acid, or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid, or malonic acidor by using other methods known in the art such as ion exchange. Othersalts include adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. Representativealkali or alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further salts include ammonium,quaternary ammonium, and amine cations formed using counterions such ashalide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and aryl sulfonate.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acids,such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids, such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound, or a salt thereof,that are associated with a solvent, usually by a solvolysis reaction.This physical association may include hydrogen bonding. Conventionalsolvents include water, methanol, ethanol, acetic acid, DMSO, THF,diethyl ether, and the like. The compounds described herein may beprepared, e.g., in crystalline form, and may be solvated. Suitablesolvates include pharmaceutically acceptable solvates and furtherinclude both stoichiometric solvates and non-stoichiometric solvates. Incertain instances, the solvate will be capable of isolation, forexample, when one or more solvent molecules are incorporated in thecrystal lattice of a crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Representative solvates includehydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2H₂O) and hexahydrates (R.6H₂O)).

A “polymer” is given its ordinary meaning as used in the art, i.e., amolecular structure comprising one or more repeat units (monomers),connected by covalent bonds. The repeat units may all be identical, orin some cases, there may be more than one type of repeat unit presentwithin the polymer. In certain embodiments, the polymer has C═C. Incertain embodiments, the polymer is prepared from ring openingmetathesis polymerization.

The term “cross-linker” refers to compounds that link one polymer chainto another by covalent bonds or ionic bonds. “Polymer chains” can referto synthetic polymers or natural polymers (such as proteins).

The term “macromonomer” refers to a macromolecule with one end-groupthat enables it to act as a monomer. Macromonomers will contribute asingle monomeric unit to a chain of the completed macromolecule.

The term “prodrugs” refer to compounds and/or polymers, includingcompounds of Formula (I) and polymers of Formula (III′) (e.g., Formula(III)), which have cleavable groups and become active by solvolysis,reduction, oxidation, or under physiological conditions, to provide thepharmaceutically active compounds in vivo. Prodrugs include polymericderivatives conjugated with the pharmaceutical active compounds known topractitioners of the art, such as, for example, to form an ester byreaction of the acid, or acid anhydride, or mixed anhydrides moieties ofthe polymer of the polymer with the hydroxyl moiety of thepharmaceutical active compound, or to form an amide prepared by theacid, or acid anhydride, or mixed anhydrides moieties of the polymerwith a substituted or unsubstituted amine of the pharmaceutically activecompound. Simple aliphatic or aromatic esters, amides, and anhydridesderived from acidic groups pendant on the polymers of this invention areparticular prodrugs. In some embodiments, the polymer incorporates onetherapeutic agent. In some embodiments, the polymer incorporates morethan one therapeutic agents.

A linker being “cleavable” refers to at least one bond in the linkerbeing able to break. In certain embodiments, at least 10%, at least 30%,at least 50%, at least 90%, at least 95%, or at least 99% (e.g., atleast 90%) of the at least one bond is able to break within 1 minute, 10minutes, 1 hour, 3 hours, 8 hours, or 24 hours, under a condition (e.g.,irradiation (e.g., irradiation with UV), presence of a reductant,physiological condition, or a combination thereof). In certainembodiments, the at least one bond is in the linker's backbone.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult, or senior adult)) and/or othernon-human animals, for example, mammals (e.g., primates (e.g.,cynomolgus monkeys, rhesus monkeys); commercially relevant mammals suchas cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds(e.g., commercially relevant birds such as chickens, ducks, geese,and/or turkeys). In certain embodiments, the animal is a mammal. Theanimal may be a male or female and at any stage of development. Anon-human animal may be a transgenic or genetically engineered animal.

The terms “administer,” “administering,” or “administration” refer toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing an inventive polymer, or a pharmaceutical compositionthereof, or a device incorporating the inventive polymer.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of a“pathological condition” (e.g., a disease, disorder, or condition, orone or more signs or symptoms thereof) described herein. In someembodiments, treatment may be administered after one or more signs orsymptoms have developed or have been observed. In other embodiments,treatment may be administered in the absence of signs or symptoms of thedisease or condition. For example, treatment may be administered to asusceptible individual prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibilityfactors). Treatment may also be continued after symptoms have resolved,for example, to delay or prevent recurrence.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response. An effectiveamount of a compound described herein may vary depending on such factorsas the desired biological endpoint, the pharmacokinetics of thecompound, the condition being treated, the mode of administration, andthe age and health of the subject. In certain embodiments, an effectiveamount is a therapeutically effective amount. In certain embodiments, aneffective amount is a prophylactic treatment. In certain embodiments, aneffective amount is the amount of a compound described herein in asingle dose. In certain embodiments, an effective amount is the combinedamounts of a compound described herein in multiple doses.

A “therapeutically effective amount” is an amount sufficient to providea therapeutic benefit in the treatment of a condition or to delay orminimize one or more symptoms associated with the condition. Atherapeutically effective amount of an inventive polymer means an amountof therapeutic agent, alone or in combination with other therapies,which provides a therapeutic benefit in the treatment of the condition.The term “therapeutically effective amount” can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes of thecondition, or enhances the therapeutic efficacy of another therapeuticagent.

A “prophylactically effective amount” is an amount sufficient to preventa condition, or one or more symptoms associated with the condition orprevent its recurrence. A prophylactically effective amount of acompound means an amount of a therapeutic agent, alone or in combinationwith other agents, which provides a prophylactic benefit in theprevention of the condition. The term “prophylactically effectiveamount” can encompass an amount that improves overall prophylaxis orenhances the prophylactic efficacy of another prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis or diseases associated withangiogenesis, inflammatory diseases, autoinflammatory diseases, andautoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An example of a pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites.

The term “metastasis,” “metastatic,” or “metastasize” refers to thespread or migration of cancerous cells from a primary or original tumorto another organ or tissue and is typically identifiable by the presenceof a “secondary tumor” or “secondary cell mass” of the tissue type ofthe primary or original tumor and not of that of the organ or tissue inwhich the secondary (metastatic) tumor is located. For example, aprostate cancer that has migrated to bone is said to be metastasizedprostate cancer and includes cancerous prostate cancer cells growing inbone tissue.

The term “cancer” refers to a malignant neoplasm (Stedman's MedicalDictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia,1990). Exemplary cancers include, but are not limited to, acousticneuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma(e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma);appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g.,cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast); brain cancer (e.g., meningioma,glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma),medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer(e.g., cervical adenocarcinoma); choriocarcinoma; chordoma;craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer,colorectal adenocarcinoma); connective tissue cancer; epithelialcarcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g.,uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenstrim's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphomalleukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemiallymphoma asdescribed above; and multiple myeloma), heavy chain disease (e.g., alphachain disease, gamma chain disease, mu chain disease); hemangioblastoma;hypopharynx cancer; inflammatory myofibroblastic tumors; immunocyticamyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor,renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, smallcell lung cancer (SCLC), non-small cell lung cancer (NSCLC),adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g.,systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS);mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera(PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM)a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronicmyelocytic leukemia (CML), chronic neutrophilic leukemia (CNL),hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g.,neurofibromatosis (NF) type 1 or type 2, schwannomatosis);neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor(GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of thepenis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT);plasma cell neoplasia; paraneoplastic syndromes; intraepithelialneoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectalcancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g.,squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basalcell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestinecancer; sweat gland carcinoma; synovioma; testicular cancer (e.g.,seminoma, testicular embryonal carcinoma); thyroid cancer (e.g.,papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC),medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvarcancer (e.g., Paget's disease of the vulva).

The term “angiogenesis” refers to the formation and growth of new bloodvessels. Normal angiogenesis occurs in the body of a healthy subjectduring wound healing and for restoring blood flow to tissues afterinjury. The body controls angiogenesis through a number of means, e.g.,angiogenesis-stimulating growth factors and angiogenesis inhibitors.Many disease states, such as cancer, diabetic blindness, age-relatedmacular degeneration, rheumatoid arthritis, and psoriasis, arecharacterized by abnormal (i.e., increased or excessive) angiogenesis.Abnormal angiogenesis refers to angiogenesis greater than that in anormal body, especially angiogenesis in an adult not related to normalangiogenesis (e.g., menstruation or wound healing). Abnormalangiogenesis can result in new blood vessels that feed diseased tissuesand/or destroy normal tissues, and in the case of cancer, the newvessels can allow tumor cells to escape into the circulation and lodgein other organs (tumor metastases).

The term “ratiometric” refers to the situation where C₁ ^(i) issubstantially equal to C₀ ^(i), wherein C₀ ^(i) refers to the ratio ofthe amount of a first agent before the first agent is delivered to asubject, tissue, or cell, to the total amount of two or more agents(including the first agent) before the two or more agents are deliveredto the subject, tissue, or cell; and C₁ ^(i) refers to the ratio of theamount of the first agent that is delivered to the subject, tissue, orcell, to the total amount of the two or more agents (including the firstagent) that are delivered to the subject, tissue, or cell. In certainembodiments, the delivery of each one of the two or more agents isratiometric.

The term “orthogonal” refers to the situation where a first agent and asecond agent, each of which is included in a Pt-BASP described herein,is independently released from the Pt-BASP. In certain embodiments,under condition A, the first agent, but not the second agent, isreleased from the Pt-BASP. For example, an orthogonal release ororthogonal delivery of the first and second agents includes: undercondition A, the first agent, but not the second agent, is released fromthe Pt-BASP; under condition B, the second agent, but not the firstagent, is released from the Pt-BASP. The release or delivery of thefirst and second agents is not orthogonal when, for example, undercondition C, both the first and second agents are released from thePt-BASP.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

FIG. 1 shows an exemplary synthesis of Pt-BASPs loaded with anoxaliplatin prodrug crosslinker oxPt-XL, irinotecan (IRT), and5-fluorouracil (5FU).

FIG. 2 shows structures of exemplary therapeutic agents: oxPt-XL,camptothecin (CPT), irinotecan (IRT), and SN-38.

FIG. 3 shows Dynamic Light Scattering (DLS) data and a negativelystained Transmission Electron Microscopy (TEM) image of a BASP preparedfrom oxPt-XL and PEG-MM.

FIG. 4 shows release of cisplatin and oxaliplatin from BASPs in theabsence and presence of intracellular concentration (about 5 mM) ofglutathione (GSH) reducing agent.

FIG. 5 shows CAOV3 cell viability studies in the presence of cisplatinand oxaliplatin crosslinkers and BASPs.

FIG. 6 shows total mouse body weight after injection of two differentdoses, 4.5 mg and 1.8 mg, of oxaliplatin BASP every 5 days for 25 days.

FIG. 7 shows passive tumor acculmulation of Cy5.5-labeled oxaliplatinBASP.

FIG. 8 shows the synthesis of an Oxaliplatin Crosslinker (OxPtXL).

FIGS. 9A to 9C show chemical structures of: i) topoisomerase I/IIinhibitors, camptothecin (CPT) and doxorubicin (DOX) (FIG. 9A); ii) DNAcrosslinkers/intercalators, cisplatin (cisPt) and oxaplatin (oxPt) (FIG.9B); and iii) various macromonomer (MM)-crosslinkers (XL) (FIG. 9C). Thehighlighted functional groups of CPT and DOX indicate where the drug isconjugated to the MM.

FIG. 10 shows the general scheme for the synthesis of the reporteddrug-loaded brush polymers, followed by cross-linking with thebis-norbornene functionalized Pt(IV) prodrug to afford brush-arm starpolymers (BASPs) used for in vitro and in vivo efficacy studies.

FIG. 11 shows the ¹³C nuclear magnetic resonance (NMR) of OxPtXL (100MHz, DMSO-d₆, 298K).

FIG. 12 shows the ¹⁹⁵Pt NMR of OxPtXL (86 MHz, DMSO-d₆, 298K).

FIGS. 13A to 13D show TEM images of: i) CPT-oxPt-dilute DOX (0.2%)3-drug BASP (FIG. 13A); ii) CPT-AcetalXL 1-drug BASP (FIG. 13B); iii)DOX-AcetalXL 1-drug BASP (FIG. 13C); and iv) PEG-AcetalXL no-drug BASP(FIG. 13D).

FIGS. 14A to 14B show a signature assay heat map (FIG. 14A) whichillustrates the effect that UV-triggered release of DOX has on themechanism of action of the three-drug-loaded nanoparticle andcorresponding principal component analysis (FIG. 14B).

FIG. 15 shows different views of paraffin-embedded and H&E stained livercross sections obtained from control mice (top panel),nanoparticle-treated mice with tumors possessing 1 cm and 0.5 cmdiameters (middle panel), and free drug treated mice (bottom panel).

FIG. 16 shows different views of paraffin-embedded and H&E stained left(L) and right (R) tumor cross sections obtained from control mice (toppanel), nanoparticle-treated mice with tumors possessing 1 cm and 0.5 cmdiameters (middle panel), and free drug treated mice (bottom panel).

FIGS. 17A to 17B show the pharmacokinetics of NP-OxPt containing 1%Cy5.5-MM injected (4.5 mg/dose; 18 mg/kg) in BALB/c mice over a 126 hperiod (FIG. 17A) and tumor localization in NCR-NU mice injected withNP-OxPt containing 1% Cy5.5-MM (FIG. 17B).

FIG. 18 shows the blood panel analysis of biomarkers associated withNCR-NU mice treated with NP-3D-OxPt (#114 bars: Chronic; #19 bars:Acute), the free drug combination (#5 bars: DOX-CPT-OxPt), or 5% glucosesolutions. B/C=BUN/Creatinine.

FIGS. 19A to 19C show: i) tumor localization of NP-3D-OxPt-Cy5.5 inNCR-NU mice injected with 5 mg of the three-drug-loaded nanoparticle andmonitoring (excitation at 675 nm; emission at 720 nm) theepifluorescence at 3 and 20 h in an IVIS whole animal imaging system(FIG. 19A); ii) a tumor volume plot and treatment schedule for the invivo efficacy evaluation of mice possessing 1 cm in diametersubcutaneous xenograft tumors (FIG. 19B); and iii) a survival curveillustrating the survival probability of the nanoparticle treated miceversus the control mice that were only injected with 5% glucosesolutions (FIG. 19C).

FIGS. 20A to 20F show heat maps and classification of: i) doxorubicinnative, prodrug and nanoparticles (FIG. 20A); ii) camptothecin native,prodrug and nanoparticles (FIG. 20B); iii) cisplatin native, prodrug andnanoparticles (FIG. 20C); iv) oxaliplatin native, prodrug andnanoparticles (FIG. 20D); v) corresponding principal component analysisof the RNAi signatures from native, prodrug and nanoparticles ofdoxorubicin, camptothecin, cisplatin and oxaliplatin as well asrepresentative drugs from transcription/translation (Txn/Tln) inhibitor,Top2 poison, Top1 poison, and DNA cross-linker reference set categories(FIG. 20E); and vi) a heat map depicting response of Top1 and Top2AshRNA bearing cells to treatment with doxorubicin or camptothecin freedrug or nanoparticles (FIG. 20F).

FIGS. 21A to 21C show the constrained linear regression prediction ofthe impact of the following combination nanoparticles on the mechanismof action: i) UV-triggered doxorubicin macromonomers with or without UV(FIG. 21A); ii) very diluted UV-triggered doxorubicin macromonomers withor without UV (FIG. 21B); and iii) normal doxorubicin macromonomers withor without UV (FIG. 21C).

FIG. 22 shows the synthesis of cisplatin(cisPt)-Doxorubicin(DOX)-camptothecin (CPT) nanoparticles prepared bycross-linking with the bis-norbornene functionalized Pt(IV) prodrug toafford brush-arm star polymers (BASPs) used for in vitro and in vivoefficacy studies. The DLS histograms for drug-loaded BASPs are asfollows: cisplatin only (1), cisplatin and CPT (2a), cisplatin and DOX(2b), and cisplatin and CPT and DOX (3). The TEM images are ofpositively (top panel) and negatively (bottom panel) stainedcisPt-DOX-CPT nanoparticles.

FIGS. 23A to 23D show characterization data for NP-3D-OxPt-Cy5.5 BASPsthrough TEM images (FIGS. 23A to 23B), and OxPt-CPT-DOX BASPs throughdigital light scattering (DLS) analysis (FIG. 23C) and gel permeationchromatography (GPC) analysis (FIG. 23D).

FIGS. 24A to 24D show tumor localization of NP-3D-OxPt-Cy5.5 in NCR-NUmice injected with 5 mg of the three-drug-loaded nanoparticle andmonitoring (excitation at 675 nm; emission at 720 nm) theepifluorescence at 3 and 20 h in an IVIS whole animal imaging system(FIG. 24A), a tumor volume plot and treatment schedule for the in vivoevaluation of mice possessing 0.5 cm in diameter subcutaneous xenografttumors (FIG. 24B), a survival curve illustrating the survivalprobability of the nanoparticle treated mice versus the control micethat were only injected with 5% glucose solutions (FIG. 24C), and theaverage body mass of the nanoparticle, control, and free drug treatedgroups monitored over the course of 60 days (FIG. 24D). Mice treatedwith the free drug formulation show significant (>10%) weight loss,whereas the NP treated and vehicle control mice demonstrate consistentbody masses.

FIG. 25 shows the treatment schedule of Mouse #105 with CPT-DOX-OxPtover a 21 day period. After a 12 week period, nearly complete tumorreduction was observed.

FIG. 26 shows different views of H&E stained left (L) and right (R)tumor cross sections obtained from a control mouse (FIG. 26, top panel),H&E stained liver cross sections obtained from acute and chronic mice(FIG. 26, middle panel), and H&E stained right (R) tumor cross sectionsobtained from acute and chronic mice (FIG. 26, bottom panel).

FIG. 27 shows the general scheme for iterative exponential growth(IEG+).

FIGS. 28A to 28D show the general synthesis of syndiotactic 32-unithomopolymer blocks (FIG. 28A) and further analysis using matrix-assistedlaser desorption/ionization (MALDI) (FIG. 28B), GPC (FIG. 28C), and ¹HNMR (FIG. 28D).

FIG. 29 shows the general synthesis of pseudo-diblock 32-unitalternating copolymer blocks and further analysis using MALDI and GPC.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Oxaliplatin and related derivatives are widely used in cancerchemotherapy. Significant adverse reactions related to oxaliplatin andrelated derivatives frequently limits the use of higher doses to achievetheir maximum antineoplastic effects. The present invention providesplatinum-based brush-arm star polymers (Pt-BASPs) and methods for thecontrolled delivery of oxaliplatin and related compounds. In certainembodiments, the Pt-BASPs are loaded with a bis-norbornene oxaliplatincrosslinker (oxPt-XL). In certain embodiments, the Pt-BASPs are loadedwith oxPt-XL and one or more therapeutic, diagnostic, or prophylacticagents for multi-agent delivery.

Oxaliplatin or its Derivative Crosslinkers

In one aspect, the present invention provides a platinum complex ofFormula (I):

or salts thereof,wherein:

each instance of R^(N1) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, a nitrogen protecting group, or two R^(N1) aretaken with the intervening atoms to form a heterocyclic ring;

each instance of R^(N2) is independently hydrogen, substituted orunsubstituted C₁₋₆ alkyl, or a nitrogen protecting group, or or twoR^(N2) are taken with the intervening atoms to form a heterocyclic ring;

L^(N) is a linker selected from the group consisting of substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted arylene, substituted or unsubstitutedheterarylene, substituted or unsubstituted cycloalkylene, substituted orunsubstituted heterocyclylene, and combinations thereof; and eachinstance of n is 1, 2, 3, 4, 5, or 6.

As generally defined herein, each instance of R^(N1) is independentlyhydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogen protectinggroup, or two R^(N1) are taken with the intervening atoms to form aheterocyclic ring. In certain embodiments, at least one instance ofR^(N1) is hydrogen. In certain embodiments, each instance of R^(N1) ishydrogen. In certain embodiments, at least one instance of R^(N1) isoptionally substituted C₁₋₆ alkyl. In certain embodiments, each instanceof R^(N1) is optionally substituted C₁₋₆ alkyl. In certain embodiments,R^(N1) is substituted C₁₋₆ alkyl. In certain embodiments, R^(N1) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(N1) is methyl. Incertain embodiments, R^(N1) is ethyl. In certain embodiments, R^(N1) isa nitrogen protecting group. In certain embodiments, two R^(N1) aretaken with the intervening atoms to form a heterocyclic ring.

As generally defined herein, each instance of R^(N2) is independentlyhydrogen, optionally substituted C₁₋₆ alkyl, or a nitrogen protectinggroup, or two R^(N2) are taken with the intervening atoms to form aheterocyclic ring, or R^(N1) and R^(N2) are taken with the interveningatoms to form a heterocyclic ring. In certain embodiments, at least oneinstance of R^(N2) is hydrogen. In certain embodiments, each instance ofR^(N2) is hydrogen. In certain embodiments, at least one instance ofR^(N2) is optionally substituted C₁₋₆ alkyl. In certain embodiments,each instance of R^(N2) is optionally substituted C₁₋₆ alkyl. In certainembodiments, R^(N2) is substituted C₁₋₆ alkyl. In certain embodiments,R^(N2) is unsubstituted C₁₋₆ alkyl. In certain embodiments, R^(N2) ismethyl. In certain embodiments, R^(N2) is ethyl. In certain embodiments,R^(N2) is a nitrogen protecting group. In certain embodiments, twoR^(N2) are taken with the intervening atoms to form a heterocyclic ring.In certain embodiments, R^(N1) and R^(N2) are taken with the interveningatoms to form a heterocyclic ring.

In certain embodiments, R^(N1) and R^(N2) are the same. In certainembodiments, R^(N1) and R^(N2) are different. In certain embodiments,all instances of R^(N1) and R^(N2) are hydrogen. In certain embodiments,at least one instance of R^(N1) is hydrogen and at least one instance ofR^(N2) is not hydrogen. In certain embodiments, at least one instance ofR^(N1) is hydrogen and at least one instance of R^(N2) is optionallysubstituted C₁₋₆ alkyl. In certain embodiments, at least one instance ofR^(N1) is hydrogen and at least one instance of R^(N2) is substitutedC₁₋₆ alkyl. In certain embodiments, at least one instance of R^(N1) ishydrogen and at least one instance of R^(N2) is unsubstituted C₁₋₆alkyl. In certain embodiments, at least one instance of R^(N1) ishydrogen and at least one instance of R^(N2) is methyl, ethyl, orpropyl. In certain embodiments, at least one instance of R^(N1) and atleast one instance of R^(N2) are each independently optionallysubstituted C₁₋₆ alkyl. In certain embodiments, at least one instance ofR^(N1) and at least one instance of R^(N2) are each independentlysubstituted C₁₋₆ alkyl. In certain embodiments, at least one instance ofR^(N1) and at least one instance of R^(N2) are each independentlyunsubstituted C₁₋₆ alkyl. In certain embodiments, at least one instanceof R^(N1) and at least one instance of R^(N2) are each independently ismethyl, ethyl, or propyl. In certain embodiments, at least one instanceof R^(N1) and at least one instance of R^(N2) are each independently anitrogen protecting group.

As generally defined herein, L^(N) is a linker selected from the groupconsisting of substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstituted arylene,substituted or unsubstituted heterarylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocyclylene, andcombinations (e.g., combination of two, three, or four) thereof. Incertain embodiments, L^(N) is substituted or unsubstituted alkylene. Incertain embodiments, L^(N) is substituted alkylene. In certainembodiments, L^(N) is unsubstituted alkylene (e.g., methylene, ethylene,or propylene). In certain embodiments, L^(N) is substituted orunsubstituted heteroalkylene. In certain embodiments, L^(N) issubstituted or unsubstituted arylene. In certain embodiments, L^(N) issubstituted or unsubstituted phenylene. In certain embodiments, L^(N) issubstituted or unsubstituted heterarylene. In certain embodiments, L^(N)is substituted or unsubstituted 5-membered or 6-membered heterarylene.In certain embodiments, L^(N) is substituted or unsubstitutedcycloalkylene. In certain embodiments, L^(N) is substituted orunsubstituted cyclohexylene. In certain embodiments, L^(N) issubstituted or unsubstituted cyclohexylene, wherein the point ofattachments are 1- and 4-positions. In certain embodiments, L^(N) issubstituted or unsubstituted cyclohexylene, wherein the point ofattachments are 1- and 3-positions. In certain embodiments, L^(N) issubstituted or unsubstituted cyclohexylene, wherein the point ofattachments are 1- and 2-positions.

In certain embodiments, L^(N) is substituted or unsubstitutedcycloalkylene and R^(N1) and R^(N2) are the same. In certainembodiments, L^(N) is substituted or unsubstituted cyclohexylene andR^(N1) and R^(N2) are hydrogen. In certain embodiments, L^(N) issubstituted or unsubstituted cyclohexylene, wherein the point ofattachments are 1- and 4-positions, and R^(N1) and R^(N2) are hydrogen.

In certain embodiments, the number of atoms in the shortest backbone ofL^(N) is 1. In certain embodiments, the number of atoms in the shortestbackbone of L^(N) is 2. In certain embodiments, the number of atoms inthe shortest backbone of L^(N) is 3. In certain embodiments, the numberof atoms in the shortest backbone of L^(N) is 4.

As generally defined herein, n is 1, 2, 3, 4, 5, or 6. In certainembodiments, n is 1. In certain embodiments, n is 2. In certainembodiments, n is 3. In certain embodiments, n is 4. In certainembodiments, n is 5. In certain embodiments, n is 6.

In certain embodiments, the platinum complexes of Formula (I) areprodrugs of the oxaliplatin. The Pt—O bond can be cleaved by a reducingagent in vivo to release oxaliplatin. In certain embodiments, theplatinum complex of Formula (I) is used as a crosslinker to preparepolymers for the controlled release of oxaliplatin. In certainembodiments, the platinum complex of Formula (I) is used as acrosslinker to prepare Pt-BASP.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (I-a):

or a salt thereof,wherein:

each instance of R^(A) is independently hydrogen, halogen, substitutedor unsubstituted alkyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl; and each instance of RBis independently hydrogen, halogen, substituted or unsubstituted alkyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl;

or two instances of R^(B) are joined to form a substituted orunsubstituted, carbocyclic ring, or substituted or unsubstituted,heterocyclic ring.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (I-b):

or a salt thereof.

In certain embodiments, at least one instance of R^(A) is hydrogen. Incertain embodiments, each instance of R^(A) is hydrogen. In certainembodiments, at least one instance of R^(A) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, at least one instance of R^(A) is unsubstitutedalkyl (e.g., unsubstituted C₁₋₆ alkyl, such as methyl, ethyl, orpropyl). In certain embodiments, at least one instance of R^(A) issubstituted alkyl (e.g., substituted C₁₋₆ alkyl). In certainembodiments, at least one instance of R^(A) is halogen (e.g., F).

In certain embodiments of Formulae (I-a)-(I-b), at least one instance ofR^(A) is hydrogen. In certain embodiments of Formulae (I-a)-(I-b), bothinstances of R^(A) are hydrogen. In certain embodiments of Formulae(I-a)-(I-b), at least one instance of R^(A) is substituted orunsubstituted alkyl. In certain embodiments of Formulae (I-a)-(I-b), atleast one instance of R^(A) is unsubstituted alkyl. In certainembodiments of Formulae (I-a)-(I-b), at least one instance of R^(A) issubstituted alkyl.

In certain embodiments, at least one instance of R^(B) is hydrogen. Incertain embodiments, each instance of R^(B) is hydrogen. In certainembodiments, at least one instance of R^(B) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, at least one instance of R^(B) is unsubstitutedalkyl (e.g., unsubstituted C₁₋₆ alkyl, such as methyl, ethyl, orpropyl). In certain embodiments, at least one instance of R^(B) issubstituted alkyl (e.g., substituted C₁₋₆ alkyl). In certainembodiments, at least one instance of R^(B) is halogen (e.g., F).

In certain embodiments of Formulae (I-a)-(I-b), at least one instance ofR^(B) is hydrogen. In certain embodiments of Formulae (I-a)-(I-b), bothinstances of R^(B) are hydrogen. In certain embodiments of Formulae(I-a)-(I-b), at least one instance of R^(B) is substituted orunsubstituted alkyl. In certain embodiments of Formulae (I-a)-(I-b), atleast one instance of R^(B) is unsubstituted alkyl. In certainembodiments of Formulae (I-a)-(I-b), at least one instance of R^(B) issubstituted alkyl. In certain embodiments of Formulae (I-a)-(I-b), twoR^(B) are joined to form a substituted or unsubstituted, carbocyclicring, or substituted or unsubstituted, heterocyclic ring. In certainembodiments of Formulae (I-a)-(I-b), two R^(B) are joined to form asubstituted or unsubstituted carbocyclic ring. In certain embodiments ofFormulae (I-a)-(I-b), two R^(B) are joined to form a substituted orunsubstituted cyclohexyl ring.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (I-c):

or a salt thereof,wherein:

Ring A is a substituted or unsubstituted, monocyclic, 3- to 7-memberedcarbocyclic ring;

each instance of R^(C) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))S(═O)R^(a), —N(R^(a))S(═O)OR^(a), —N(R^(a))S(═O)N(R^(a))₂,—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂OR^(a), —N(R^(a))S(═O)₂N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

each instance of R^(a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring; and

u is an integer between 0 and 8, inclusive.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (I-d):

or a salt thereof.

In certain embodiments of Formulae (I-c) and (I-d), Ring A is asubstituted or unsubstituted cyclopropyl ring. In certain embodiments ofFormulae (I-c) and (I-d), Ring A is a substituted or unsubstitutedcyclobutyl ring. In certain embodiments of Formulae (I-c) and (I-d),Ring A is a substituted or unsubstituted cyclopentyl ring. In certainembodiments of Formulae (I-c) and (I-d), Ring A is a substituted orunsubstituted cyclohexyl ring. In certain embodiments of Formulae (I-c)and (I-d), Ring A is a substituted or unsubstituted cycloheptyl ring.

In certain embodiments of Formula (I-d), R^(A) is hydrogen. In certainembodiments of Formula (I-d), R^(A) is substituted or unsubstitutedalkyl. In certain embodiments of Formula (I-d), R^(A) is unsubstitutedalkyl (e.g., methyl, ethyl, or propyl). In certain embodiments ofFormula (I-d), R^(A) is substituted alkyl.

In certain embodiments, at least one instance of R^(C) is hydrogen. Incertain embodiments, each instance of R^(C) is hydrogen. In certainembodiments, at least one instance of R^(C) is substituted orunsubstituted alkyl (e.g., substituted or unsubstituted C₁₋₆ alkyl). Incertain embodiments, at least one instance of R^(C) is unsubstitutedalkyl (e.g., unsubstituted C₁₋₆ alkyl, such as methyl, ethyl, orpropyl). In certain embodiments, at least one instance of R^(C) issubstituted alkyl (e.g., substituted C₁₋₆ alkyl). In certainembodiments, at least one instance of R^(C) is halogen (e.g., F). Incertain embodiments, each instance of R^(C) is the same.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (I-e):

or a salt thereof.

In certain embodiments of Formulae (I-c)-(I-e), u is 0. In certainembodiments of Formulae (I-c)-(I-e), u is 2. In certain embodiments ofFormulae (I-c)-(I-e), u is 3. In certain embodiments of Formulae(I-c)-(I-e), u is 4. In certain embodiments of Formulae (I-c)-(I-e), uis 5. In certain embodiments of Formulae (I-c)-(I-e), u is 6. In certainembodiments of Formulae (I-c)-(I-e), u is 7. In certain embodiments ofFormulae (I-c)-(I-e), u is 8.

In certain embodiments, the platinum complex of Formula (I) is ofFormula (I-f):

or a salt thereof.

As generally used herein,

encompasses a racemic moiety or any stereoisomer thereof. In certainembodiments, at least one instance of

is of one of the following formulae:

In certain embodiments, each instance of

is of one of the following formulae:

In certain embodiments, each instance of

is of the formula:

In certain embodiments, the provided platinum complex is of the formula:

In certain embodiments, the provided platinum complex is of the formula:

The platinum complex of Formula (I) can be prepared using the generalmethodology shown in Scheme 1. Details of the synthetic procedures aredescribed in the Examples below.

In one embodiments, the invention provides methods of preparing aplatinum complex of Formula (I), the method comprising steps of:

(a) oxidizing a compound of Formula (S-I) with an oxidant

to yield a compound of Formula (S-2):

wherein R^(N1), R^(N2), L^(N), and n are as defined herein; and

-   -   (b) coupling the compound of Formula (S-2) with a compound of        Formula (S-3):

to yield a platinum complex of Formula (I).

In certain embodiments, the oxidant used in step (a) can oxidize Pt (II)to Pt (IV) with two hydroxyl groups under suitable oxidization condition(Hall et al., J. Biol. Inorg. Chem. 2003, 8, 726). In certainembodiments, the oxidant is H₂O₂.

In certain embodiments, an activator is present in the coupling reactionin step (b). The activator converts the compound of Formula (S-3) to anactivated ester for the coupling reaction. Examples of useful activatorsare dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC/HCl),diphenylphosphorylazide (DPPA), carbonyldiimidazole (CDI),diethylcyanophosphonate (DEPC),benzotriazole-1-yloxy-trispyrrolidinophosphonium (DIPCI),benzotriazole-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate(PyBOP), 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu),dimethylaminopyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAt),hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphonate (HATU),O-benzotriazole-1-yl-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), 3,4-dihydro-3-hydrodi-4-oxa-1,2,3-benzotriazine (Dhbt). Incertain embodiments, the activator is DCC.

The activator is used in an amount of about 1 to 20 equivalents of thecompound of Formula (S-2). In certain embodiments, the activator is usedin an amount of about 1 to 10 equivalents. In certain embodiments, theactivator is used in an amount of about 1 to 5 equivalents.

Examples of useful solvents in the coupling reaction are DMSO, DMF,methylene chloride. The coupling reaction can be conducted at 0 to 50°C. In certain embodiments, the coupling reaction is conducted at roomtemperature for about 10 min to about 30 hours. In certain embodiments,the coupling reaction is conducted for about 15 minutes to about 24hours.

Platinum-Based Brush-Arm Star Polymers (Pt-BASPs)

The present invention provides platinum-based brush-arm star polymers(Pt-BASP) using the “brush-first” ring-opening metathesis polymerization(ROMP). The brush-first method involves sequential copolymerization oftwo functional monomers, a polymeric macromonomer (MM) followed by amultifunctional crosslinker, to generate a unimolecular micelle-likenanostructure with a core comprised of oxaliplatin or a derivativethereof crosslinker and a corona comprised of the MM. Synthesis ofPt-BASPs is generally described in International Application No.PCT/US2014/033554 filed Apr. 9, 2014, which is incorporated by referencein its entirety herein.

A Pt-BASP described herein includes oxaliplatin or a derivative thereofattached to the rest of the Pt-BASP through ester bonds. Oxaliplatin isa clinically approved chemotherapeutic agent that includes aplatinum(II) core, the bidentate ligand, 1,2-diaminocyclohexane, and abidentate oxalate group.

In addition to oxaliplatin or a derivative thereof, a Pt-BASP describedherein may include one or more additional agents that are notoxaliplatin or a derivative thereof to form multi-agent-loaded (e.g.,multi-drug-loaded) Pt-BASPs. The described Pt-BASPs are advantageousover known nanoparticle (NP)-based delivery systems. NP-basedcombination cancer therapy has the potential to overcome the toxicityand poorly controlled dosing of traditional systemic combinationtherapies (Hu, C. M. J.; Zhang, L. F. Biochem. Pharmacol. 2012, 83,1104; Yan, Y.; Bjornmalm, M.; Caruso, F. ACS Nano 2013, 7, 9512; Ma, L.;Kohli, M.; Smith, A. ACS Nano 2013, 7, 9518). Though NP-basedtherapeutics for cancer therapy have been the subject of numerousinvestigations over the past several decades (Duncan, R. Nat. Rev. DrugDiscovery 2003, 2, 347; Peer et al. Nat. Nanotechnol. 2007, 2, 751;Wolinsky, J. B.; Grinstaff, M. W. Adv. Drug Delivery Rev. 2008, 60,1037; Davis, M. E.; Chen, Z.; Shin, D. M. Nat. Rev. Drug Discovery 2008,7, 771; Kwon, G. S.; Kataoka, K. Adv. Drug Delivery Rev. 2012, 64, 237),ratiometric, synchronized release of multiple drugs from single NPscaffolds remains a challenge (Sengupta et al. Nature 2005, 436, 568;Lammers et al. Biomaterials 2009, 30, 3466; Kolishetti, N.; Dhar, S.;Valencia, P. M.; Lin, L. Q.; Karnik, R.; Lippard, S. J.; Langer, R.;Farokhzad, O. C. Proc. Natl. Acad. Sci. U.S.A 2010, 107, 17939; Aryal,S.; Hu, C. M. J.; Zhang, L. F. Mol. Pharm. 2011, 8, 1401). Many reportednanoparticle architectures for delivery, e.g., liposomes, micelles, anddendrimers, are not readily amenable to controlled incorporation andrelease of multiple drugs.

In contrast, the Pt-BASPs described herein are able to deliver multipleagents (e.g., cisplatin and one or more other agents) ratiometrically.The agents included in a Pt-BASP may show different therapeutic,diagnostic, and/or prophylactic effects on a subject, tissue, or cell.For example, a Pt-BASP may include two or more therapeutic agents(including oxaliplatin or a derivative thereof), and the therapeuticagents may show different anti-proliferative activities (e.g.,anti-cancer activities) at each therapeutic agent's maximum tolerateddose (MTD). A key benefit of single nanoparticle combination therapy isthe ability to deliver multiple drugs at a precise ratio to a subject,tissue, or cell, while minimizing undesired effects (e.g., toxicity)associated with multiple drug combinations. To achieve the maximumtherapeutic index in a multi-drug combination therapy, simultaneousdosing of each drug at or near each drug's MTD would be ideal. A Pt-BASPdescribed herein may include multiple drugs at or near each drug's MTDbefore the Pt-BASP is delivered to a subject, tissue, or cell, releasethe multiple drugs at or near each drug's MTD into the subject, tissue,or cell after delivery, and therefore achieve the maximum therapeuticindex. In certain embodiments, Pt-BASPs described herein includecamptothecin (CPT) and oxaliplatin or a derivative thereof (e.g.,oxPt-XL). In certain embodiments, Pt-BASPs described herein includeirinotecan (IRT) and oxaliplatin or a derivative thereof (e.g.,oxPt-XL). In certain embodiments, Pt-BASP described herein include SN-38and oxaliplatin or a derivative thereof (e.g. oxPt-XL). In certainembodiments, Pt-BASPs described herein include 5-FU and oxaliplatin or aderivative thereof (e.g., oxPt-XL). In certain embodiments, Pt-BASPsdescribed herein include IRT, 5-FU, and oxaliplatin or a derivativethereof. In certain embodiments, Pt-BASPs described herein include CPT,5-FU, and oxaliplatin or a derivative thereof. In certain embodiments,Pt-BASPs described herein include SN-38, 5-FU, and oxaliplatin or aderivative thereof.

The Pt-BASPs described herein are also able to deliver multiple agentsorthogonally. Different chemical and/or physical conditions may beemployed to individually release the multiple agents upon delivery. Theconvergent synthesis of Pt-BASPs allow the attachment of differentagents to the Pt-BASPs through different linkers (e.g., linkerscleavable by reduction, such as Pt—O bonds; hydrolysable linkers, suchas ester bonds; and photo-cleavable linkers, such as the moiety

wherein the moiety may be further substituted). For example, oxaliplatinmay be released from a Pt-BASP by a reduction reaction of the Pt—Obonds; and other agents included in the Pt-BASP may be released from thePt-BASP under chemical and/or physical conditions that are differentfrom the reduction reaction. In certain embodiments, an agent, otherthan oxaliplatin or a derivative thereof, included in a Pt-BASP isreleased from the Pt-BASP by hydrolysis (e.g., hydrolysis under acidicconditions). In certain embodiments, an agent, other than oxaliplatin ora derivative thereof, included in a Pt-BASP is released from the Pt-BASPby irradiation with ultraviolet light (UV).

The Pt-BASPs described herein can be directly constructed usingcarefully designed drug-conjugates as building blocks, and noself-assembly is required for preparing the Pt-BASPs. The methods forpreparing the Pt-BASPs described herein involves ring-opening metathesispolymerization (ROMP) (Liu et al. J. Am. Chem. Soc. 2012, 134, 16337;Liu, J.; Gao, A. X.; Johnson, J. A. J Vis Exp 2013, e50874). In certainembodiments, the Pt-BASPs described herein are prepared bypolymerization of norbornene-terminated macromonomers (MMs) followed byin situ crosslinking with bis-norbornene crosslinkers. The preparationmethods described herein are versatile and have little limitations,e.g., in terms of the different agents that can be built into thePt-BASPs. In certain embodiments, an agent that can be built into thePt-BASPs includes addressable functional groups that are compatible withROMP. In certain embodiments, the invention provides Pt-BASPs preparedby Method A′ including the steps of:

(a) reacting a macromonomer of Formula (III′):

or a salt thereof, with a metathesis catalyst to form a polymerizationmixture, wherein:

-   -   a is an integer from 1 to 10, inclusive;    -   each instance of b is independently an integer from 1 to 10,        inclusive;    -   c is an integer from 1 to 200, inclusive;    -   e is 0, 1, 2, 3, 4, 5, or 6;    -   each instance of L is independently —O—, —S—, —NR^(La)—,        —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,        —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,        trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C═C—,        —OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—,        —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂-, —S(═O)₂NR^(La)—,        —NR^(La)S(═O)₂—, a peptide, a cleavable linker, a polymer, or a        substituted or unsubstituted C₁₋₁₀ hydrocarbon chain, optionally        wherein one or more carbon units of the hydrocarbon chain is        independently replaced with substituted or unsubstituted phenyl,        substituted or unsubstituted triazolyl, —O—, —S—, —NR^(La)—,        —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,        —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,        trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—,        —OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—,        —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂-, —S(═O)₂NR^(La)—, or        —NR^(La)S(═O)₂—, wherein each instance of R^(La) is        independently hydrogen, substituted or unsubstituted C₁₋₁₀        alkyl, or a nitrogen protecting group, and wherein each        occurrence of R^(Lb) is independently selected from the group        consisting of hydrogen, halogen, substituted or unsubstituted        alkyl, substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,        substituted or unsubstituted heterocyclyl, substituted or        unsubstituted aryl, and substituted or unsubstituted heteroaryl,        or two R^(Lb) groups are joined to form a substituted or        unsubstituted carbocyclic or substituted or unsubstituted        heterocyclic ring, or R^(La) and R^(Lb) are joined to form a        substituted or unsubstituted heterocyclic ring;

each instance of M is independently hydrogen or an agent (e.g.,pharmaceutical agent (e.g., therapeutic, diagnostic, or prophylacticagent)); and

(b) contacting the polymerization mixture from step (a) with a platinumcomplex of Formula (I) (e.g., a solution of a platinum complex ofFormula (I)).

In certain embodiments, the invention provides Pt-BASPs prepared byMethod A including the steps of:

(a) reacting a macromonomer of Formula (III)

with a metathesis catalyst to form a polymerization mixture;wherein:

-   -   a is an integer from 1 to 10, inclusive;    -   each instance of b is independently an integer from 1 to 5        inclusive;    -   c is an integer from 30 to 100 inclusive;    -   e is 0, 1, 2, 3, or 4;    -   each instance of L is independently —O—, —S—, —NR^(La)—,        —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,        —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,        trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—,        —OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—,        —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(La)—,        —NR^(La)S(═O)₂—, a peptide, a cleavable linker, or an optionally        substituted C₁₋₁₀ hydrocarbon chain, optionally wherein one or        more carbon units of the hydrocarbon chain is replaced with —O—,        —S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —OC(═O)—,        —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,        trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—,        —OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—,        —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(La)—, or        —NR^(La)S(═O)₂—, wherein each instance of R^(La) is        independently hydrogen, optionally substituted C₁₋₁₀ alkyl, or a        nitrogen protecting group, and wherein each occurrence of R^(Lb)        is independently selected from the group consisting of hydrogen,        halogen, optionally substituted alkyl, optionally substituted        alkenyl, optionally substituted alkynyl, optionally substituted        carbocyclyl, optionally substituted heterocyclyl, optionally        substituted aryl, and optionally substituted heteroaryl, or two        R^(Lb) groups are joined to form an optionally substituted        carbocyclic or optionally substituted heterocyclic ring, or        R^(La) and R^(Lb) are joined to form an optionally substituted        heterocyclic ring; and

each instance of M is independently hydrogen or a pharmaceutical agent(e.g., therapeutic, diagnostic, or prophylactic agent); and

(b) contacting the polymerization mixture from step (a) with a platinumcomplex of Formula (I) (e.g., a solution of a platinum complex ofFormula (I)).

In certain embodiments, M in the macromonomer is oxaliplatin or aderivative thereof. In certain embodiments, M in the macromonomer isoxPt-XL. In Method A′ (e.g., Method A), step (a) may be performed in thepresence of a non-agent-loaded MM, such as a macromonomer of Formula(IV):

In certain embodiments, the molar ratio of a non-agent-loaded MM to thecombined agents (including oxPt-XL) is about 0.01:1, about 0.3:1, about0.67:1, about 1:1, about 1.5:1, about 3:1, about 10:1, about 30:1, orabout 100:1, inclusive. In certain embodiments, the molar ratio of anon-agent-loaded macromonomer to the combined agents (includingcisplatin) is about 0.67:1, inclusive.

In certain embodiments, the provided Pt-BASPs are prepared by Method B′including the steps of:

(a) reacting a first macromonomer of Formula (III′), or a salt thereof,with a second macromonomer of Formula (III′), or a salt thereof:

in the presence of a metathesis catalyst to form a polymerizationmixture, wherein a, L, M, b, e, and c are as described herein, providedthat M in the first macromonomer is different from M in the secondmacromonomer; and

(b) contacting the polymerization mixture from step (a) with a platinumcomplex of Formula (I) (e.g., a solution of a platinum complex ofFormula (I)).

In certain embodiments, the provided Pt-BASPs are loaded with more thanone therapeutic, diagnostic, or prophylactic agents other thanoxaliplatin or a derivative thereof and can be prepared by Method Bincluding the steps of:

(a) reacting a first macromonomer of Formula (III) with a secondmacromonomer of Formula (III)

in the presence of a metathesis catalyst to form a polymerizationmixture,wherein:

a is an integer from 1 to 10, inclusive;

each instance of b is independently an integer from 1 to 5 inclusive;

c is an integer from 1 to 100 inclusive;

e is 0, 1, 2, 3, or 4;

each instance of L is independently —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—,—C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—,—OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, a peptide, a cleavable linker, or anoptionally substituted C₁₋₁₀ hydrocarbon chain, optionally wherein oneor more carbon units of the hydrocarbon chain is replaced with —O—, —S—,—NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance of R^(La) isindependently hydrogen, optionally substituted C₁₋₁₀ alkyl, or anitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(Lb) groups are joined to form anoptionally substituted carbocyclic or optionally substitutedheterocyclic ring, or R^(La) and R^(Lb) are joined to form an optionallysubstituted heterocyclic ring; each instance of M is independentlyhydrogen or a pharmaceutical agent (e.g., therapeutic, diagnostic, orprophylactic agent); and M in the first macromonomer is different from Min the second macromonomer; and

(b) contacting the polymerization mixture from step (a) with a platinumcomplex of Formula (I) (e.g., a solution of a platinum complex ofFormula (I)).

In Method B′ (e.g., Method B), step (a) may be performed in the presenceof a non-agent-loaded MM, such as a macromonomer of Formula (IV):

In certain embodiments, the non-agent-loaded MM is macromonomer PEG-MM.In certain embodiments of the Pt-BASPs loaded with more than onetherapeutic, diagnostic, or prophylactic agents, Ms in the first andsecond macromonomers are different. In certain embodiments of thePt-BASPs loaded with more than one therapeutic, diagnostic, orprophylactic agents, Ms in the first and second macromonomers are thesame. In certain embodiments of the Pt-BASPs loaded with more than onetherapeutic, diagnostic, or prophylactic agents, at one instance of Msin the first MM and at least one instance of Ms in the second MM aredifferent from each other. In certain embodiments, Ms in the first andsecond macromonomers are not oxaliplatin or a derivative thereof (e.g.,oxPt-XL). In certain embodiments of the Pt-BASPs loaded with more thanone therapeutic, diagnostic, or prophylactic agents, Ms in the first andsecond macromonomers are different therapeutic agents. In certainembodiments, M in the first macromonomer is camptothecin, and M in thesecond macromonomer is 5-FU. In certain embodiments, M in the firstmacromonomer is IRT, and M in the second macromonomer is 5-FU. Incertain embodiments, M in the first macromonomer is SN-38, and M in thesecond macromonomer is 5-FU.

As generally defined herein, a is an integer from 1 to 10, inclusive. Incertain embodiments, a is 1. In certain embodiments, a is 2. In certainembodiments, a is 3. In certain embodiments, a is 4. In certainembodiments, a is 5. In certain embodiments, a is 6. In certainembodiments, a is 7. In certain embodiments, a is 8. In certainembodiments, a is 9. In certain embodiments, a is 10.

As generally defined herein, each instance of b is independently aninteger from 1 to 10, inclusive. In certain embodiments, b is an integerfrom 1 to 5, inclusive. In certain embodiments, b is 1. In certainembodiments, b is 2. In certain embodiments, b is 3. In certainembodiments, b is 4. In certain embodiments, b is 5. In certainembodiments, b is 6. In certain embodiments, b is 7. In certainembodiments, b is 8. In certain embodiments, b is 9. In certainembodiments, b is 10.

As generally defined herein, c is an integer from 1 to 200, inclusive.In certain embodiments, c is an integer from 1 to 100, inclusive. Incertain embodiments, c is an integer from 1 to 29, inclusive. In certainembodiments, c is an integer from 30 to 100, inclusive. In certainembodiments, c is an integer from 40 to 90, inclusive. In certainembodiments, c is an integer from 50 to 80, inclusive. In certainembodiments, c is an integer from 60 to 70, inclusive. In certainembodiments, c is about 65. In certain embodiments, c is about 66. Incertain embodiments, c is about 67. In certain embodiments, c is about68. In certain embodiments, c is about 69. In certain embodiments, c isabout 70. In certain embodiments, c is an integer from 101 to 200,inclusive.

As generally defined herein, e is 0, 1, 2, 3, 4, 5, or 6. In certainembodiments, e is 0, 1, 2, 3, or 4. In certain embodiments, e is 0. Incertain embodiments, e is 1. In certain embodiments, e is 2. In certainembodiments, e is 3. In certain embodiments, e is 4. In certainembodiments, e is 5. In certain embodiments, e is 6.

As generally defined herein, each instance of L is independently —O—,—S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—,—OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—,—C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—,—OS(═O)₂—, —S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, a peptide, a cleavablelinker, a polymer, or a substituted or unsubstituted C₁₋₃₀ hydrocarbonchain, optionally wherein one or more carbon units of the hydrocarbonchain is independently replaced with substituted or unsubstitutedphenyl, substituted or unsubstituted triazolyl, —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance of R^(La) isindependently hydrogen, substituted or unsubstituted C₁₋₁₀ alkyl, or anitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl, or two R^(Lb) groups are joined to form a substituted orunsubstituted carbocyclic or substituted or unsubstituted heterocyclicring, or R^(La) and R^(Lb) are joined to form a substituted orunsubstituted heterocyclic ring.

In certain embodiments, linker L is —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—,—C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—,—OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, a peptide, a cleavable linker, or anoptionally substituted C₁₋₁₀ hydrocarbon chain, optionally wherein oneor more carbon units of the hydrocarbon chain is replaced with —O—, —S—,—NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance of R^(La) isindependently hydrogen, optionally substituted C₁₋₁₀ alkyl, or anitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, and optionallysubstituted heteroaryl, or two R^(Lb) groups are joined to form anoptionally substituted carbocyclic or optionally substitutedheterocyclic ring, or R^(La) and R^(Lb) are joined to form an optionallysubstituted heterocyclic ring.

In certain embodiments, L is an optionally substituted C₁₋₁₀ hydrocarbonchain, optionally wherein one or more carbon units of the hydrocarbonchain is replaced with —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—,—C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—,—OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—. In certain embodiments, at leastone instance of L is a peptide. In certain embodiments, L is a peptideconsisting of between 2 and 50, between 2 and 30, between 2 and 20,between 2 and 10, between 2 and 5, between 5 and 50, between 5 and 30,between 5 and 20, between 5 and 10, between 10 and 50, between 10 and30, between 10 and 20, between 20 and 50, between 20 and 30, or between30 and 50, inclusive, amino acids (e.g., natural amino acids). Incertain embodiments, at least one instance of L is cleavable linker. Incertain embodiments, L is a photo-cleavable linker. In certainembodiments, L is not a photo-cleavable linker. In certain embodiments,L is not a photo-cleavable linker. In certain embodiments, L is a linkercleavable by hydrolysis (e.g., under physiological conditions). Incertain embodiments, L is a linker cleavable by reduction. In certainembodiments, at least one instance of L is a polymer (e.g., a polymerwhose M_(w) is between 2,000 and 1,000,000, g/mol, inclusive).

In certain embodiments, at least one instance of L is a substituted orunsubstituted C₁₋₃₀ hydrocarbon chain (e.g., substituted orunsubstituted C₆₋₂₀ hydrocarbon chain), wherein one or more (e.g., two,three, four, five, or six) carbon units of the hydrocarbon chain isindependently replaced with substituted or unsubstituted phenyl,substituted or unsubstituted triazolyl, —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—.

In certain embodiments, at least one instance of L is a substituted orunsubstituted C₁₋₃₀ hydrocarbon chain (e.g., substituted orunsubstituted C₆₋₂₀ hydrocarbon chain), wherein:

one or more (e.g., two) carbon units of the hydrocarbon chain isreplaced with substituted or unsubstituted triazolyl (e.g.,

wherein the nitrogen atom labelled with “*” is attached (e.g., directlyor indirectly) to M); and

optionally one or more (e.g., two, three, four, or five) carbon units ofthe hydrocarbon chain is independently replaced with substituted orunsubstituted phenyl, —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—,—C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—,—OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C═C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—.

In certain embodiments, at least one instance of L is a substituted orunsubstituted C₁₋₃₀ hydrocarbon chain (e.g., substituted orunsubstituted C₆₋₂₀ hydrocarbon chain), wherein:

one or more (e.g., two) carbon units of the hydrocarbon chain isreplaced with substituted or unsubstituted triazolyl (e.g.,

wherein the nitrogen atom labelled with “*” is attached (e.g., directlyor indirectly) to M);

one or more (e.g., two) carbon units of the hydrocarbon chain isreplaced with substituted or unsubstituted phenyl; and

optionally one or more (e.g., two, three, or four) carbon units of thehydrocarbon chain is independently replaced with —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—.

In certain embodiments, when at least one instance of L is a substitutedC₁₋₃₀ hydrocarbon chain (e.g., substituted C₁₋₁₀ hydrocarbon chain),optionally wherein one or more carbon units of the hydrocarbon chain isindependently replaced as described herein, the substituents on theC₁₋₃₀ hydrocarbon chain (e.g., C₁₋₁₀ hydrocarbon chain) areindependently halogen or substituted or unsubstituted C₁₋₆ alkyl. Incertain embodiments, when at least one instance of L is a substitutedC₁₋₃₀ hydrocarbon chain (e.g., substituted C₁₋₁₀ hydrocarbon chain),optionally wherein one or more carbon units of the hydrocarbon chain isindependently replaced as described herein, the substituents on theC₁₋₃₀ hydrocarbon chain (e.g., C₁₋₁₀ hydrocarbon chain) areindependently halogen or unsubstituted C₁₋₆ alkyl.

In certain embodiments, L is of one of the following formulae:

wherein:

each instance of the carbon atom labeled with “*” is attached to M;

each instance of R^(E) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))S(═O)R^(a), —N(R^(a))S(═O)OR^(a), —N(R^(a))S(═O)N(R^(a))₂,—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂OR^(a), —N(R^(a))S(═O)₂N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂;

each instance of R^(a) is independently hydrogen, substituted orunsubstituted acyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring;

each instance of k is independently 0, 1, 2, 3, or 4;

each instance of p is independently an integer from 1 to 10, inclusive;

each instance of q is independently an integer from 1 to 10, inclusive;

each instance of g is independently an integer from 1 to 10, inclusive;and

each instance of h is independently an integer from 1 to 10, inclusive.

In certain embodiments, each instance of L is the same. In certainembodiments, at least two instances of L are different from each other.

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-a):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-b):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-c):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-d):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-e):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-f):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-g):

In certain embodiments, the macromonomer of Formula (III) is of Formula(III-h):

As generally defined herein, each instance of M is independentlyhydrogen or an agent. In certain embodiments, the agent is a smallmolecule (optionally wherein the molecular weight of the small moleculeis not more than 2,000 g/mol). In certain embodiments, the agent is aprotein or peptide. In certain embodiments, the agent is apolynucleotide. In certain embodiments, each instance of M isindependently hydrogen or a pharmaceutical agent. In certainembodiments, M is hydrogen or a therapeutic, diagnostic, or prophylacticagent. In certain embodiments, M is hydrogen. In certain embodiments, Mis not hydrogen. In certain embodiments, at least one instance of M is apharmaceutical agent. In certain embodiments, M is a therapeutic,diagnostic, or prophylactic agent. In certain embodiments, M is atherapeutic agent. Examples of therapeutic moieties include, but are notlimited to, antimicrobial agents, analgesics, antinflammatory agents,counterirritants, coagulation modifying agents, diuretics,sympathomimetics, anorexics, antacids and other gastrointestinal agents;antiparasitics, antidepressants, antihypertensives, anticholinergics,stimulants, antihormones, central and respiratory stimulants, drugantagonists, lipid-regulating agents, uricosurics, cardiac glycosides,electrolytes, ergot and derivatives thereof, expectorants, hypnotics andsedatives, antidiabetic agents, dopaminergic agents, antiemetics, musclerelaxants, para-sympathomimetics, anticonvulsants, antihistamines,beta-blockers, purgatives, antiarrhythmics, contrast materials,radiopharmaceuticals, antiallergic agents, tranquilizers, vasodilators,antiviral agents, and antineoplastic or cytostatic agents or otheragents with anticancer properties, or a combination thereof. Othersuitable therapeutic moieties include contraceptives and vitamins aswell as micro- and macronutrients. Still other examples includeantiinfectives such as antibiotics and antiviral agents; analgesics andanalgesic combinations; anorexics; antiheimintics; antiarthritics;antiasthmatic agents; anticonvulsants; antidepressants; antidiureticagents; antidiarrleals; antihistamines; antiinflammatory agents;antimigraine preparations; antinauseants; antineoplastics;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics,antispasmodics; anticholinergics; sympathomimetics; xanthinederivatives; cardiovascular preparations including calcium channelblockers and beta-blockers such as pindolol and antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary,peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hormones such as estradioland other steroids, including corticosteroids; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; and tranquilizers; and naturally derived orgenetically engineered proteins, polysaccharides, glycoproteins, orlipoproteins. In certain embodiments, at least one instance of M is ananti-cancer agent. In certain embodiments, M is an anti-cancer agent.Anti-cancer agents encompass biotherapeutic anti-cancer agents as wellas chemotherapeutic agents. Exemplary biotherapeutic anti-cancer agentsinclude, but are not limited to, interferons, cytokines (e.g., tumornecrosis factor, interferon α, interferon γ), vaccines, hematopoieticgrowth factors, monoclonal serotherapy, immunostimulants and/orimmunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growthfactors (e.g., GM-CSF) and antibodies (e.g., HERCEPTIN (trastuzumab),T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX(panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). Exemplarychemotherapeutic agents include, but are not limited to, anti-estrogens(e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g.,goscrclin and leuprolide), anti-androgens (e.g., flutamide andbicalutamide), photodynamic therapies (e.g., vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.,busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide),platinum containing compounds (e.g., cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine,vindesine, and vinorelbine), taxoids (e.g., paclitaxel or a paclitaxelequivalent) docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel,Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxelpoliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005(Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1(paclitaxel bound to the erbB2-recognizing peptide EC-1), andglucose-conjugated paclitaxel, e.g., 2′-paclitaxel methyl2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g.,etoposide, etoposide phosphate, teniposide, topotecan,9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycinC), anti-metabolites, DHFR inhibitors (e.g., methotrexate,dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenaseinhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR),ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine),uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine,ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g.,cytarabine (ara C), cytosine arabinoside, and fludarabine), purineanalogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs(e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g.,lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridiniumion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g.,actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycinB2, peplomycin), anthracycline (e.g., daunorubicin, doxorubicin,pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin,zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca²⁺ ATPaseinhibitors (e.g., thapsigargin), imatinib, thalidomide, lenalidomide,tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib(SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®,BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib(Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®),lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®),semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib(PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK),trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®),cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®),nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®),alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus(TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258,CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF-04217903, PF-02341066,PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534,JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib(AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasomeinhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g.,rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus,AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226(Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980(Genetech), SF1126 (Semafoe), and OSI-027 (OSI)), oblimersen,gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide,dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin,plicamycin, asparaginase, aminopterin, methopterin, porfiromycin,melphalan, leurosidine, leurosine, chlorambucil, trabectedin,procarbazine, discodermolide, carminomycin, aminopterin, and hexamethylmelamine. In certain embodiments, at least one instance of M iscamptothecin. In certain embodiments, at least one instance of M is IRT.In certain embodiments, at least one instance of M is SN-38. In certainembodiments, at least one instance of M is 5-FU. In certain embodiments,at least two instances of M are camptothecin and 5-FU. In certainembodiments, at least two instances of M are IRT and 5-FU. In certainembodiments, at least two instances M are SN-38 and 5-FU. In certainembodiments, at least three instances of M are IRT, 5-FU, andoxaliplatin or a derivative thereof. In certain embodiments, at leastthree instances of M are CPT, 5-FU, and oxaliplatin or a derivativethereof. In certain embodiments, at least three instances of M areSN-38, 5-FU, and oxaliplatin or a derivative thereof.

In certain embodiments, M is a diagnostic agent. Exemplary diagnosticagents include, but are not limited to, fluorescent molecules; gases;metals; commercially available imaging agents used in positron emissionstomography (PET), computer assisted tomography (CAT), single photonemission computerized tomography, x-ray, fluoroscopy, and magneticresonance imaging (MRI); and contrast agents. Examples of suitablematerials for use as contrast agents in MRI include gadolinium chelates,as well as iron, magnesium, manganese, copper, and chromium. Examples ofmaterials useful for CAT and x-ray imaging include iodine-basedmaterials. In certain embodiments, the diagnostic agent is used inmagnetic resonance imaging (MRI), such as iron oxide particles orgadolinium complexes. Gadolinium complexes that have been approved forclinical use include gadolinium chelates with DTPA, DTPA-BMA, DOTA andHP-DO3A which are reviewed in Aime, et al. (Chemical Society Reviews(1998), 27:19-29), the entire teachings of which are incorporated hereinby reference.

In certain embodiments, M is a prophylactic agent. Prophylactic agentsthat can be included in the conjugates of the invention include, but arenot limited to, antibiotics, nutritional supplements, and vaccines.Vaccines may comprise isolated proteins or peptides, inactivatedorganisms and viruses, dead organisms and viruses, genetically alteredorganisms or viruses, and cell extracts. Prophylactic agents may becombined with interleukins, interferon, cytokines, and adjuvants such ascholera toxin, alum, Freund's adjuvant.

In certain embodiments, each instance of M is the same. In certainembodiments, at least two instances of M are different from each other.In certain embodiments, at least three instances of M are different fromeach other. In certain embodiments, at least four instances of M aredifferent from each other.

M can be conjugated to the macromonomer using any suitable conjugationtechnique. For instance, EDC-NHS chemistry(1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride andN-hydroxysuccinimide), or a reaction involving a maleimide or acarboxylic acid, which can be conjugated to one end of a thiol, anamine, or a similarly functionalized polyether. The conjugation can beperformed in an organic solvent, such as, but not limited to, methylenechloride, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran,acetone, or the like. Specific reaction conditions can be determined bythose of ordinary skill in the art using no more than routineexperimentation.

In another set of embodiments, a conjugation reaction may be performedby reacting the agent that includes a hydroxyl, thiol, or amino groupwith a polymer comprising a carboxylic acid functional group. Such areaction may occur as a single-step reaction, i.e., the conjugation isperformed with or without using intermediates such asN-hydroxysuccinimide or a maleimide. The conjugation reaction betweenthe amine-containing, thiol-containing, or hydroxyl-containing moietyand the carboxylic acid-terminated polymer may be achieved in oneembodiment, by adding the amine-containing, thiol-containing, orhydroxyl-containing moiety, solubilized in an organic solvent such as,but not limited to, dichloromethane, acetonitrile, chloroform,tetrahydrofuran, acetone, formamide, dimethylformamide, pyridines,dioxane, or dimethysulfoxide, to a solution containing the carboxylicacid-terminated polymer. The carboxylic acid-terminated polymer may becontained within an organic solvent such as, but not limited to,dichloromethane, acetonitrile, chloroform, dimethylformamide,tetrahydrofuran, or acetone. Reaction between the amine-containingmoiety and the carboxylic acid-terminated polymer may occurspontaneously in some cases. Unconjugated macromonomers may be washedaway after such reactions, and the polymer may be precipitated insolvents such as, for instance, ethyl ether, hexane, methanol, orethanol.

The synthesis of Pt-BASPs involves ROMP of MM in step (a) and ROMP ofthe platinum complex in step (b). In certain embodiments, the ROMPcatalyst is a tungsten (W), molybdenum (Mo), or ruthenium (Ru) catalyst.In certain embodiments, the ROMP catalyst is a ruthenuim catalyst. ROMPcatalysts useful in the synthetic methods described herein includecatalysts as depicted below, and as described in Grubbs et al., Acc.Chem. Res. 1995, 28, 446-452; U.S. Pat. No. 5,811,515; Schrock et al.,Organometallics (1982) 1 1645; Gallivan et al., Tetrahedron Letters(2005) 46:2577-2580; Furstner et al., J. Am. Chem. Soc. (1999) 121:9453;and Chem. Eur. J. (2001) 7:5299; the entire contents of each of whichare incorporated herein by reference.

In certain embodiments, the ROMP catalyst is a Grubbs catalyst. Incertain embodiments, the Grubbs catalyst is selected from the groupconsisting of:

-   -   Benzylidenebis-(tricyclohexylphosphine)-dichlororuthenium        (X=Cl);    -   Benzylidenebis-(tricyclohexylphosphine)-dibromoruthenium (X=Br);    -   Benzylidenebis-(tricyclohexylphosphine)-diiodoruthenium (X=I);

-   -   1,3-(Bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)        (tricyclohexyl-phosphine)ruthenium (X=Cl; R=cyclohexyl);    -   1,3-(Bis(mesityl)-2-imidazolidinylidene)dibromo-(phenylmethylene)        (tricyclohexyl-phosphine)ruthenium (X=Br; R=cyclohexyl);    -   1,3-(Bis(mesityl)-2-imidazolidinylidene)diiodo-(phenylmethylene)        (tricyclohexyl-phosphine)ruthenium (X=I; R=cyclohexyl);    -   1,3-(Bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)        (triphenylphosphine)ruthenium (X=Cl; R=phenyl);    -   1,3-(Bis(mesityl)-2-imidazolidinylidene)dichloro-(phenylmethylene)        (tribenzylphosphine)ruthenium (X=Cl; R=benzyl);

In certain embodiments, the ROMP catalyst is a Grubbs-Hoveyda catalyst.In certain embodiments, the Grubbs-Hoveyda catalyst is selected from thegroup consisting of:

In certain embodiments, the ROMP catalyst is selected from the groupconsisting of:

In certain embodiments, the ROMP catalyst is of the formula:

The ROMP can be conducted in one or more aprotic solvents. The term“aprotic solvent” means a non-nucleophilic solvent having a boilingpoint range above ambient temperature, preferably from about 25° C. toabout 190° C. at atmospheric pressure. In certain embodiments, theaprotic solvent has a boiling point from about 80° C. to about 160° C.at atmospheric pressure. In certain embodiments, the aprotic solvent hasa boiling point from about 80° C. to about 150° C. at atmosphericpressure. Examples of such solvents are methylene chloride,acetonitrile, toluene, DMF, diglyme, THF, and DMSO.

The ROMP can be quenched with a vinyl ether of the formula

Each of R^(V1), R^(V2), R^(V3), and R^(V4) is independently optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted phenyl, optionally substituted heterocyclyl, or optionallysubstituted heteroaryl. In certain embodiments, R^(V1) is optionallysubstituted alkyl, and R^(V2), R^(V3), and R^(V4) are hydrogen. Incertain embodiments, R^(V1) is unsubstituted alkyl, and R^(V2), R^(V3),and R^(V4) are hydrogen. In certain embodiments, R^(V1) is substitutedalkyl, and R^(V2), R^(V3), and R^(V4) are hydrogen. In certainembodiments, R^(V1) is methyl, and R^(V2), R^(V3), and R^(V4) arehydrogen. In certain embodiments, R^(V1) is ethyl, and R^(V2), R^(V3),and R^(V4) are hydrogen. In certain embodiments, R^(V1) is propyl, andR^(V2), R^(V3), and R^(V4) are hydrogen. In certain embodiments, R^(V1)is optionally substituted alkenyl, and R^(V2), R^(V3), and R^(V4) arehydrogen. In certain embodiments, R^(V1) is unsubstituted alkenyl, andR^(V2), R^(V3), and R^(V4) are hydrogen. In certain embodiments, R^(V1)is vinyl, and R^(V2), R^(V3), and R^(V4) are hydrogen. In certainembodiments, at least one of R^(V1), R^(V2), R^(V3), and R^(V4) isconjugated with a diagnostic agent as defined above. In certainembodiments, the ROMP is quenched by ethyl vinyl ether. Excess ethylvinyl ether can be removed from the Pt-BASPs by vacuum.

The Pt-BASPs can be multi-agent loaded star polymers. In certainembodiments, the inventive Pt-BASPs are capable of releasing multiplechemotherapeutic agents for combination therapy. In certain embodiments,the Pt-BASPs are capable of releasing two chemotherapeutic agents. Incertain embodiments, the Pt-BASPs are capable of releasing threechemotherapeutic agents. In certain embodiments, the Pt-BASPs arecapable of releasing four chemotherapeutic agents. In certainembodiments, the Pt-BASPs are capable of releasing five chemotherapeuticagents. In certain embodiments, the Pt-BASPs incorporate only aplatinum-based agent which is introduced from the platinum-based complexcrosslinkers. In certain embodiments, the inventive Pt-BASPs incorporateonly cisplatin. In certain embodiments, the Pt-BASPs incorporate one ormore therapeutic, diagnostic, or prophylactic agents. The one or moretherapeutic, diagnostic, or prophylactic agents are introduced frommacromonomers in the synthesis of Pt-BASPs. In certain embodiments, atherapeutic agent is incorporated in the macromonomer. In certainembodiments, an anti-cancer agent is incorporated in the macromonomer.In certain embodiments, the macromonomer is camptothecin (CPT)macromonomer. In certain embodiments, the macromonomer is IRTmacromonomer. In certain embodiments, the macromonomer is 5-FUmacromonomer. In certain embodiments, the macromonomer is SN-38macromonomer. In certain embodiments, the macromonomer is doxorubicin(DOX) macromonomer. In certain embodiments, the inventive Pt-BASPsincorporate oxaliplatin or a derivative thereof and CPT. In certainembodiments, the inventive Pt-BASPs incorporate oxaliplatin or aderivative thereof and IRT. In certain embodiments, the inventivePt-BASPs incorporate oxaliplatin or a derivative thereof and 5-FU. Incertain embodiments, the inventive Pt-BASPs incorporate an oxaliplatinprodrug, CPT, and 5-FU. In certain embodiments, the inventive Pt-BASPsincorporate an oxaliplatin prodrug, IRT, and 5-FU. In certainembodiments, the inventive Pt-BASPs incorporate an oxaliplatin prodrug,SN-38, and 5-FU. In certain embodiments, the one or more therapeutic,diagnostic, or prophylactic agents are connected to Pt-BASPs by aphotocleavable linker. In certain embodiments, the inventive Pt-BASPsincorporate a diagnostic agent and a platinum therapeutic agent. Incertain embodiments, the inventive Pt-BASPs incorporate a prophylacticagent and a platinum therapeutic agent.

In some cases, the Pt-BASPs are of the form of nanoparticles, i.e., theparticle have a characteristic dimension of less than about 1micrometer, where the characteristic dimension of a particle is thediameter of a perfect sphere having the same volume as the particle. Incertain embodiments, the Pt-BASP particle has a characteristic dimensionof less than about 300 nm. In certain embodiments, the Pt-BASP particlehas a characteristic dimension of less than about 200 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension of lessthan about 150 nm. In certain embodiments, the Pt-BASP particle has acharacteristic dimension of less than about 100 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension of lessthan about 50 nm. In certain embodiments, the Pt-BASP particle has acharacteristic dimension of less than about 30 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension of lessthan about 20 nm. In certain embodiments, the Pt-BASP particle has acharacteristic dimension of less than about 10 nm. In certainembodiments, the Pt-BASP particle has a characteristic dimension between6 and 250 nm, inclusive. In certain embodiments, the Pt-BASP particlehas a characteristic dimension between 8 and 200 nm, inclusive. Incertain embodiments, the Pt-BASP particle has a characteristic dimensionbetween 12 and 200 nm, inclusive. In certain embodiments, the Pt-BASPparticle has a characteristic dimension between 50 and 200 nm,inclusive.

In certain embodiments, the Pt-BASPs are biodegradable, i.e., thepolymer is able to degrade, chemically and/or biologically, within aphysiological environment, such as within the body. For instance, thepolymer may be one that hydrolyzes spontaneously upon exposure to water(e.g., within a subject), the polymer may degrade upon exposure to heat(e.g., at temperatures of about 37° C.). Degradation of a polymer mayoccur at varying rates, depending on the polymer or copolymer used. Forexample, the half-life of the polymer (the time at which 50% of thepolymer is degraded into monomers and/or other nonpolymeric moieties)may be on the order of days, weeks, months, or years, depending on thepolymer. The polymers may be biologically degraded, e.g., by enzymaticactivity or cellular machinery, in some cases, for example, throughexposure to a lysozyme (e.g., having relatively low pH). In some cases,the polymers may be broken down into monomers and/or other nonpolymericmoieties that cells can either reuse or dispose of without significanttoxic effect on the cells (for example, polylactide may be hydrolyzed toform lactic acid, polyglycolide may be hydrolyzed to form glycolic acid,etc.).

In certain embodiments, the solvents in step (a) is the same as thesolvent of the platinum complex solution in step (b). In certainembodiments, the solvents in step (a) is different from the solvent ofthe platinum complex solution in step (b). Exemplary solvents for step(a) and platinum complex solution include, but are not limited to,methylene chloride, acetonitrile, chloroform, dimethylformamide,tetrahydrofuran, and acetone. Specific reaction conditions can bedetermined by those of ordinary skill in the art using no more thanroutine experimentation.

In certain embodiments of one type of macromonomer in Pt-BASPs, theamount of all the macromonomers, the platinum complex crosslinker, andthe metathesis catalyst is of the molar ratio m:N:1, wherein m is aninteger from 1 to 20, inclusive; and N is an integer from 1 to 20,inclusive. In certain embodiments, m is an integer from 3 to 12inclusive. In certain embodiments, m is 1. In certain embodiments, m is2. In certain embodiments, m is 3. In certain embodiments, m is 4. Incertain embodiments, m is 5. In certain embodiments, m is 6. In certainembodiments, m is 7. In certain embodiments, m is 8. In certainembodiments, m is 9. In certain embodiments, m is 10. In certainembodiments, m is 11. In certain embodiments, m is 12. In certainembodiments, N is an integer from 1 to 10 inclusive. In certainembodiments, N is 1. In certain embodiments, N is 2. In certainembodiments, N is 3. In certain embodiments, N is 4. In certainembodiments, N is 5. In certain embodiments, N is 6. In certainembodiments, N is 7. In certain embodiments, N is 8. In certainembodiments, N is 9. In certain embodiments, N is 10. In certainembodiments, the amount of macromonomer, platinum complex crosslinker,and metathesis catalyst is of the ratio 5:3:1. In certain embodiments,the amount of macromonomer, platinum complex crosslinker, and metathesiscatalyst is of the molar ratio 5:5:1. In certain embodiments, the amountof macromonomer, platinum complex crosslinker, and metathesis catalystis of the molar ratio 5:7:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 7:3:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 7:5:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 7:7:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 11:1:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 11:3:1. In certain embodiments, the amount ofmacromonomer, platinum complex crosslinker, and metathesis catalyst isof the molar ratio 11:5:1.

In certain embodiments, the molar ratio of the first macromonomer to themetathesis catalyst is between 1:1 to 20:1, inclusive; the molar ratioof the second macromonomer to the metathesis catalyst is between 1:1 to20:1, inclusive; and the molar ratio of the platinum complex to themetathesis catalyst is between 1:1 to 20:1, inclusive. In certainembodiments, the molar ratio of the first macromonomer to the metathesiscatalyst is between 1:1 to 10:1, inclusive; the molar ratio of thesecond macromonomer to the metathesis catalyst is between 1:1 to 10:1,inclusive; and the molar ratio of the platinum complex to the metathesiscatalyst is between 1:1 to 10:1, inclusive. In certain embodiments, themolar ratio of the first macromonomer to the metathesis catalyst isbetween 1:1 to 5:1, inclusive; the molar ratio of the secondmacromonomer to the metathesis catalyst is between 1:1 to 5:1,inclusive; and the molar ratio of the platinum complex to the metathesiscatalyst is between 1:1 to 5:1, inclusive.

In certain embodiments of multi-agent loaded Pt-BASPs, the amount of thefirst macromonomer, second macromonomer, and platinum complexcrosslinker is of the molar ratio of m1:m2:N, wherein m1 and m2 are eachindependently an integer from 1 to 20, inclusive; and N is an integerfrom 1 to 20, inclusive. In certain embodiments, the amount of the firstmacromonomer, second macromonomer, and platinum complex crosslinker isof the molar ratio of 3:4:3. In certain embodiments, the amount of thefirst macromonomer, second macromonomer, and platinum complexcrosslinker is of the molar ratio of 4:3:3. In certain embodiments ofmore than one types of macromonomers in the multi-agent loaded Pt-BASPs,the amount of the first macromonomer, second macromonomer, and platinumcomplex crosslinker is of the molar ratio of m1:m2:N:1, wherein m1 andm2 are each independently an integer from 1 to 20, inclusive; and N isan integer from 1 to 20, inclusive. In certain embodiments, the amountof the first macromonomer, second macromonomer, and platinum complexcrosslinker is of the molar ratio of 3:4:3:1. In certain embodiments,the amount of the first macromonomer, second macromonomer, and platinumcomplex crosslinker is of the molar ratio of 4:3:3:1.

Exposure to physiologically relevant conditions can lead to the Pt-BASPsdegradation and controlled, extended release of platinum-based agents.In certain embodiments, the release rate can increased by addition ofGSH. In vitro cytotoxicity assays demonstrates that Pt-BASPs effectivelykill cancer cells (FIG. 5).

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprisingPt-BASPs, as described herein, and optionally a pharmaceuticallyacceptable excipient. In certain embodiments, the Pt-BASPs are providedin an effective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the Pt-BASPs into association witha carrier and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60),polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate(Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate(Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80)),polyoxyethylene esters (e.g., polyoxyethylene monostearate (MYRJ 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., Cremophor™),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (BRIJ 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, PLURONIC F-68, Poloxamer-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(VEEGUM), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. In certainembodiments, the preservative is an antioxidant. In other embodiments,the preservative is a chelating agent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS,PHENONIP, methylparaben, GERMALL 115, GERMABEN II, NEOLONE, KATHON, andEUXYL.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugates of theinvention are mixed with solubilizing agents such as Cremophor™,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes. Solid compositions of a similar type can beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugar as well as high molecular weightpolethylene glycols and the like.

Dosage forms for topical and/or transdermal administration of a compoundof this invention may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants and/or patches. Generally, thePt-BASPs are admixed under sterile conditions with a pharmaceuticallyacceptable carrier and/or any needed preservatives and/or buffers as canbe required. Additionally, the present invention contemplates the use oftransdermal patches, which often have the added advantage of providingcontrolled delivery of an active ingredient to the body. Such dosageforms can be prepared, for example, by dissolving and/or dispensing theactive ingredient in the proper medium. Alternatively or additionally,the rate can be controlled by either providing a rate controllingmembrane and/or by dispersing the active ingredient in a polymer matrixand/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratethe compound in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations may, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. Formulations for topicaladministration may further comprise one or more of the additionalingredients described herein.

A pharmaceutical composition of the invention can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles ofPt-BASPs described herein. Such compositions are conveniently in theform of dry powders for administration using a device comprising a drypowder reservoir to which a stream of propellant can be directed todisperse the powder and/or using a self-propelling solvent/powderdispensing container.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions of the invention formulated for pulmonarydelivery may provide the Pt-BASPs in the form of droplets of a solutionand/or suspension. Such formulations can be prepared, packaged, and/orsold as aqueous and/or dilute alcoholic solutions and/or suspensions,optionally sterile, comprising the active ingredient, and mayconveniently be administered using any nebulization and/or atomizationdevice. Such formulations may further comprise one or more additionalingredients including, but not limited to, a flavoring agent such assaccharin sodium, a volatile oil, a buffering agent, a surface activeagent, and/or a preservative such as methylhydroxybenzoate. The dropletsprovided by this route of administration may have an average diameter inthe range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition of theinvention. Another formulation suitable for intranasal administration isa coarse powder comprising the Pt-BASPs and having an average particlefrom about 0.2 to 500 micrometers. Such a formulation is administered byrapid inhalation through the nasal passage from a container of thepowder held close to the nares.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Pt-BASPs provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular subject or organism will dependupon a variety of factors including the disease being treated and theseverity of the disorder; the activity of the specific active ingredientemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific activeingredient employed; the duration of the treatment; drugs used incombination or coincidental with the specific active ingredientemployed; and like factors well known in the medical arts.

The Pt-BASPs and compositions provided herein can be administered by anyroute, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, interdermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration).

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of the inventive polymer foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the inventive polymer may be at dosage levelssufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, fromabout 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg toabout 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, fromabout 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents. The compounds or compositions can be administeredin combination with additional pharmaceutical agents that improve theirbioavailability, reduce and/or modify their metabolism, inhibit theirexcretion, and/or modify their distribution within the body. It willalso be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies. Pharmaceuticalagents include therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Each additional pharmaceuticalagent may be administered at a dose and/or on a time schedule determinedfor that pharmaceutical agent. The additional pharmaceutical agents mayalso be administered together with each other and/or with the compoundor composition described herein in a single dose or administeredseparately in different doses. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional pharmaceutical agents and/or the desired therapeuticand/or prophylactic effect to be achieved. In general, it is expectedthat the additional pharmaceutical agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

Exemplary additional pharmaceutical agents include, but are not limitedto, anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. Pharmaceutical agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The inventive kits may be useful for treating a proliferative disease(e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benignneoplasm, angiogenesis, inflammatory disease, autoinflammatory disease,or autoimmune disease). The kits provided may comprise the Pt-BASPsdescribed herein, or a pharmaceutical composition thereof, and acontainer (e.g., a vial, ampule, bottle, syringe, and/or dispenserpackage, or other suitable container). In some embodiments, providedkits may optionally further include a second container comprising apharmaceutical excipient for dilution or suspension of an inventivepharmaceutical composition or compound. In some embodiments, theinventive pharmaceutical composition or compound provided in thecontainer and the second container are combined to form one unit dosageform.

Methods of Treatment and Uses

The present invention also provides methods of using the Pt-BASPsdescribed herein, or a pharmaceutical composition thereof, for thetreatment or prevention of a proliferative disease such as cancer (e.g.,lung cancer, large bowel cancer, pancreas cancer, biliary tract cancer,colorectal cancer, or endometrial cancer), benign neoplasm,angiogenesis, inflammatory disease, autoinflammatory disease, orautoimmune disease in a subject.

In some embodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof are useful in treating a cancer. In someembodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof, are useful to delay the onset of, slow theprogression of, or ameliorate the symptoms of cancer. In someembodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof, are administered in combination with othercompounds, drugs, or therapeutics to treat cancer.

In some embodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof are useful for treating a cancer including, but notlimited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, analcancer, angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benignmonoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma),bladder cancer, breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast), brain cancer (e.g., meningioma; glioma, e.g.,astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer,carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma),choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g.,colon cancer, rectal cancer, colorectal adenocarcinoma), epithelialcarcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma,multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g.,uterine cancer, uterine sarcoma), esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma), Ewingsarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma),familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g.,stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head andneck cancer (e.g., head and neck squamous cell carcinoma, oral cancer(e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g.,laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer,oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such asacute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acutemyelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma suchas Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkinlymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma(DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., “Waldenstrim's macroglobulinemia”), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphomalleukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma), heavy chain disease (e.g., alphachain disease, gamma chain disease, mu chain disease), hemangioblastoma,inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidneycancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma),liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma),lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer(SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung),leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis),myelodysplastic syndrome (MDS), mesothelioma, myeloproliferativedisorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM), a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)),neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), islet cell tumors), penile cancer (e.g., Paget's disease of thepenis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT),prostate cancer (e.g., prostate adenocarcinoma), rectal cancer,rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamouscell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cellcarcinoma (BCC)), small bowel cancer (e.g., appendix cancer), softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat glandcarcinoma, synovioma, testicular cancer (e.g., seminoma, testicularembryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of thethyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer),urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's diseaseof the vulva).

In some embodiments, the Pt-BASPs described herein, or a pharmaceuticalcomposition thereof, are useful in treating lung cancer, head-and-neckcancer, esophagus cancer, stomach cancer, breast cancer, pancreascancer, colorectal cancer, liver cancer, kidney cancer, prostate caner,glioblastomas, metastatic melanomas, peritoneal or pleuralmesotheliomas.

In some embodiments, the proliferative disease is a benign neoplasm. Alltypes of benign neoplasms disclosed herein or known in the art arecontemplated as being within the scope of the invention. In someembodiments, the proliferative disease is associated with angiogenesis.All types of angiogenesis disclosed herein or known in the art arecontemplated as being within the scope of the invention. In certainembodiments, the proliferative disease is an inflammatory disease. Alltypes of inflammatory diseases disclosed herein or known in the art arecontemplated as being within the scope of the invention. In certainembodiments, the inflammatory disease is rheumatoid arthritis. In someembodiments, the proliferative disease is an autoinflammatory disease.All types of autoinflammatory diseases disclosed herein or known in theart are contemplated as being within the scope of the invention. In someembodiments, the proliferative disease is an autoimmune disease. Alltypes of autoimmune diseases disclosed herein or known in the art arecontemplated as being within the scope of the invention.

In certain embodiments, the methods described herein includeadministering to a subject with an effective amount of the Pt-BASPsdescribed herein, or a pharmaceutical composition thereof. In certainembodiments, the methods described herein include implanting to asubject with an effective amount of the Pt-BASPs described herein, or apharmaceutical composition thereof.

In certain embodiments, the Pt-BASPs described herein, or apharmaceutical composition thereof, are administered in combination withone or more additional pharmaceutical agents described herein. Incertain embodiments, the additional pharmaceutical agent is ananti-cancer agent. Anti-cancer agents encompass biotherapeuticanti-cancer agents as well as chemotherapeutic agents. Exemplarybiotherapeutic anti-cancer agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g., HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR(tositumomab)). Exemplary chemotherapeutic agents include, but are notlimited to, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol),LHRH agonists (e.g., goscrclin and leuprolide), anti-androgens (e.g.,flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin(BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellinA (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.,busulfan and treosulfan), triazenes (e.g., dacarbazine, temozolomide),platinum containing compounds (e.g., cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g., vincristine, vinblastine,vindesine, and vinorelbine), taxoids (e.g., paclitaxel or a paclitaxelequivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g., etoposide, etoposidephosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate),IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin,ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g.,hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil(5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil,capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosinearabinoside, and fludarabine), purine analogs (e.g., mercaptopurine andThioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060),isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins(e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.,staurosporine), actinomycin (e.g., actinomycin D, dactinomycin),bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g., verapamil), Ca²⁺ ATPase inhibitors (e.g.,thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinaseinhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib(RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib(TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B,STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701),neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib,SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib(ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab(HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab(ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib(TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab(CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®),ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW2992 (TOVOK™), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607,ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265,DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121,XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib(VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779),everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055(AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) andOSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin,pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin,aminopterin, and hexamethyl melamine. In certain embodiments, theanti-cancer agent is abiraterone acetate (e.g., ZYTIGA), ABVD, ABVE,ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine (e.g., KADCYLA),afatinib dimaleate (e.g., GILOTRIF), aldesleukin (e.g., PROLEUKIN),alemtuzumab (e.g., CAMPATH), anastrozole (e.g., ARIMIDEX), arsenictrioxide (e.g., TRISENOX), asparaginase erwinia chrysanthemi (e.g.,ERWINAZE), axitinib (e.g., INLYTA), azacitidine (e.g., MYLOSAR, VIDAZA),BEACOPP, belinostat (e.g., BELEODAQ), bendamustine hydrochloride (e.g.,TREANDA), BEP, bevacizumab (e.g., AVASTIN), bicalutamide (e.g.,CASODEX), bleomycin (e.g., BLENOXANE), blinatumomab (e.g., BLINCYTO),bortezomib (e.g., VELCADE), bosutinib (e.g., BOSULIF), brentuximabvedotin (e.g., ADCETRIS), busulfan (e.g., BUSULFEX, MYLERAN),cabazitaxel (e.g., JEVTANA), cabozantinib-s-malate (e.g., COMETRIQ),CAF, capecitabine (e.g., XELODA), CAPOX, carboplatin (e.g., PARAPLAT,PARAPLATIN), carboplatin-taxol, carfilzomib (e.g., KYPROLIS), carmustine(e.g., BECENUM, BICNU, CARMUBRIS), carmustine implant (e.g., GLIADELWAFER, GLIADEL), ceritinib (e.g., ZYKADIA), cetuximab (e.g., ERBITUX),chlorambucil (e.g., AMBOCHLORIN, AMBOCLORIN, LEUKERAN, LINFOLIZIN),chlorambucil-prednisone, CHOP, cisplatin (e.g., PLATINOL, PLATINOL-AQ),clofarabine (e.g., CLOFAREX, CLOLAR), CMF, COPP, COPP-ABV, crizotinib(e.g., XALKORI), CVP, cyclophosphamide (e.g., CLAFEN, CYTOXAN, NEOSAR),cytarabine (e.g., CYTOSAR-U, TARABINE PFS), dabrafenib (e.g., TAFINLAR),dacarbazine (e.g., DTIC-DOME), dactinomycin (e.g., COSMEGEN), dasatinib(e.g., SPRYCEL), daunorubicin hydrochloride (e.g., CERUBIDINE),decitabine (e.g., DACOGEN), degarelix, denileukin diftitox (e.g.,ONTAK), denosumab (e.g., PROLIA, XGEVA), Dinutuximab (e.g., UNITUXIN),docetaxel (e.g., TAXOTERE), doxorubicin hydrochloride (e.g., ADRIAMYCINPFS, ADRIAMYCIN RDF), doxorubicin hydrochloride liposome (e.g., DOXIL,DOX-SL, EVACET, LIPODOX), enzalutamide (e.g., XTANDI), epirubicinhydrochloride (e.g., ELLENCE), EPOCH, erlotinib hydrochloride (e.g.,TARCEVA), etoposide (e.g., TOPOSAR, VEPESID), etoposide phosphate (e.g.,ETOPOPHOS), everolimus (e.g., AFINITOR DISPERZ, AFINITOR), exemestane(e.g., AROMASIN), FEC, fludarabine phosphate (e.g., FLUDARA),fluorouracil (e.g., ADRUCIL, EFUDEX, FLUOROPLEX), FOLFIRI,FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV,fulvestrant (e.g., FASLODEX), gefitinib (e.g., IRESSA), gemcitabinehydrochloride (e.g., GEMZAR), gemcitabine-cisplatin,gemcitabine-oxaliplatin, goserelin acetate (e.g., ZOLADEX), Hyper-CVAD,ibritumomab tiuxetan (e.g., ZEVALIN), ibrutinib (e.g., IMBRUVICA), ICE,idelalisib (e.g., ZYDELIG), ifosfamide (e.g., CYFOS, IFEX, IFOSFAMIDUM),imatinib mesylate (e.g., GLEEVEC), imiquimod (e.g., ALDARA), ipilimumab(e.g., YERVOY), irinotecan hydrochloride (e.g., CAMPTOSAR), ixabepilone(e.g., IXEMPRA), lanreotide acetate (e.g., SOMATULINE DEPOT), lapatinibditosylate (e.g., TYKERB), lenalidomide (e.g., REVLIMID), lenvatinib(e.g., LENVIMA), letrozole (e.g., FEMARA), leucovorin calcium (e.g.,WELLCOVORIN), leuprolide acetate (e.g., LUPRON DEPOT, LUPRON DEPOT-3MONTH, LUPRON DEPOT-4 MONTH, LUPRON DEPOT-PED, LUPRON, VIADUR),liposomal cytarabine (e.g., DEPOCYT), lomustine (e.g., CEENU),mechlorethamine hydrochloride (e.g., MUSTARGEN), megestrol acetate(e.g., MEGACE), mercaptopurine (e.g., PURINETHOL, PURIXAN), methotrexate(e.g., ABITREXATE, FOLEX PFS, FOLEX, METHOTREXATE LPF, MEXATE,MEXATE-AQ), mitomycin c (e.g., MITOZYTREX, MUTAMYCIN), mitoxantronehydrochloride, MOPP, nelarabine (e.g., ARRANON), nilotinib (e.g.,TASIGNA), nivolumab (e.g., OPDIVO), obinutuzumab (e.g., GAZYVA), OEPA,ofatumumab (e.g., ARZERRA), OFF, olaparib (e.g., LYNPARZA), omacetaxinemepesuccinate (e.g., SYNRIBO), OPPA, oxaliplatin (e.g., ELOXATIN),paclitaxel (e.g., TAXOL), paclitaxel albumin-stabilized nanoparticleformulation (e.g., ABRAXANE), PAD, palbociclib (e.g., IBRANCE),pamidronate disodium (e.g., AREDIA), panitumumab (e.g., VECTIBIX),panobinostat (e.g., FARYDAK), pazopanib hydrochloride (e.g., VOTRIENT),pegaspargase (e.g., ONCASPAR), peginterferon alfa-2b (e.g., PEG-INTRON),peginterferon alfa-2b (e.g., SYLATRON), pembrolizumab (e.g., KEYTRUDA),pemetrexed disodium (e.g., ALIMTA), pertuzumab (e.g., PERJETA),plerixafor (e.g., MOZOBIL), pomalidomide (e.g., POMALYST), ponatinibhydrochloride (e.g., ICLUSIG), pralatrexate (e.g., FOLOTYN), prednisone,procarbazine hydrochloride (e.g., MATULANE), radium 223 dichloride(e.g., XOFIGO), raloxifene hydrochloride (e.g., EVISTA, KEOXIFENE),ramucirumab (e.g., CYRAMZA), R-CHOP, recombinant HPV bivalent vaccine(e.g., CERVARIX), recombinant human papillomavirus (e.g., HPV)nonavalent vaccine (e.g., GARDASIL 9), recombinant human papillomavirus(e.g., HPV) quadrivalent vaccine (e.g., GARDASIL), recombinantinterferon alfa-2b (e.g., INTRON A), regorafenib (e.g., STIVARGA),rituximab (e.g., RITUXAN), romidepsin (e.g., ISTODAX), ruxolitinibphosphate (e.g., JAKAFI), siltuximab (e.g., SYLVANT), sipuleucel-t(e.g., PROVENGE), sorafenib tosylate (e.g., NEXAVAR), STANFORD V,sunitinib malate (e.g., SUTENT), TAC, tamoxifen citrate (e.g., NOLVADEX,NOVALDEX), temozolomide (e.g., METHAZOLASTONE, TEMODAR), temsirolimus(e.g., TORISEL), thalidomide (e.g., SYNOVIR, THALOMID), thiotepa,topotecan hydrochloride (e.g., HYCAMTIN), toremifene (e.g., FARESTON),tositumomab and iodine I 131 tositumomab (e.g., BEXXAR), TPF, trametinib(e.g., MEKINIST), trastuzumab (e.g., HERCEPTIN), VAMP, vandetanib (e.g.,CAPRELSA), VEIP, vemurafenib (e.g., ZELBORAF), vinblastine sulfate(e.g., VELBAN, VELSAR), vincristine sulfate (e.g., VINCASAR PFS),vincristine sulfate liposome (e.g., MARQIBO), vinorelbine tartrate(e.g., NAVELBINE), vismodegib (e.g., ERIVEDGE), vorinostat (e.g.,ZOLINZA), XELIRI, XELOX, ziv-aflibercept (e.g., ZALTRAP), or zoledronicacid (e.g., ZOMETA).

In certain embodiments, the subject being treated is a mammal. Incertain embodiments, the subject is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal such as a dog or cat. In certain embodiments, the subject is alivestock animal such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent, dog, or non-humanprimate. In certain embodiments, the subject is a non-human transgenicanimal such as a transgenic mouse or transgenic pig.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

Materials and Methods

All reagents were purchased from commercial suppliers and used withoutfurther purification unless stated otherwise. Norbornene anhydride a2¹,dihydroxy oxaliplatin-Pt(IV) a1², Grubbs 3^(rd) generation bispyridylcatalyst G3-Cat³, PEG-MM⁴, DOX-MMS, DOX-PC-MM¹, CPT-MM¹, Cy5.5-MM⁶,CisPtXL¹, and AcetalXL⁵ were prepared according to literatureprocedures. Liquid chromatography mass spectrometry (LC-MS) tandem wasperformed on a reverse-phase, C18-column using a binary solvent system(MeCN and H₂O with 0.1% CH₃COOH). Size exclusion chromatography (SEC)analyses were performed on an Agilent 1260 Infinity setup with twoShodex KD-806M columns in tandem and a 0.025 M LiBr DMF mobile phase runat 60° C. The differential refractive index (dRI) of each compound wasmonitored using a Wyatt Optilab T-rEX detector. Column chromatographywas carried out on silica gel 60F (EMD Millipore, 0.040-0.063 mm).Nuclear magnetic resonance (NMR) spectra were recorded on Bruker AVANCE111-400 spectrometer, with working frequencies of 400 (1H), 100 (¹³C)and 86 (¹⁹⁵Pt) MHz, respectively. Chemical shifts are reported in ppmrelative to the signals corresponding to the residual non-deuteratedsolvents: DMSO-d₆: 5H=2.50 and 5c=39.5 ppm. High-resolution mass spectra(HRMS) were measured on a Bruker Daltonics APEXIV 4.7 Tesla FourierTransform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR-MS) using anelectrospray ionization (ESI) source. Dynamic light scattering (DLS)measurements were performed using a Wyatt Technology Mobius DLSinstrument. Samples were prepared by diluting the stock solution (BASPnanoparticles were stored at 0° C. in THF to prevent aggregation) ineither nanopure water (MilliQ) or 5% glucose solution (also in nanopurewater); the resulting solutions were passed through a 0.4 m Nalgenefilter (PES membrane) into disposable polystyrene cuvettes, which werepre-cleaned with compressed air. Measurements were made in sets of 10acquisitions, and the average hydrodynamic diameters were calculated byfitting the DLS correlation function (Dynamics V7 software package fromWyatt Technology). TEM images were acquired using a FEI TecnaiMultipurpose TEM (G2 Spirit TWIN, 12 kV) at the MIT Center for MaterialsScience and Engineering. Sample preparation consisted of the following:5 μL of a 1.0 mg/mL aqueous solution of BASP nanoparticles was pipettedonto a carbon film-coated 200-mesh copper grid (Electron MicroscopySciences) placed on a piece of parafilm. Next, the aqueous solution wascarefully absorbed at the base of the droplet using the edge of aKimwipe, leaving behind the nanoparticles on the TEM grid. The sampleswere then stained negatively by adding a drop of 2 wt % uranyl acetate(Electronic Microscopy Sciences). After 5 min, the residual uranylacetate solution was carefully absorbed onto a Kimwipe, and the sampleswere allowed to dry completely before analysis.

RNAi signatures were performed as described previously²⁻⁴. Briefly,Eμ-Myc p19^(Arf−/−) lymphoma cells were infected at about 30% withGFP-tagged shRNAs. The cells were then treated with drug to kill 80-90%of cells as judged by propidium iodide exclusion via flow cytometry at48 h. At 72 h, GFP positivity was assessed via flow cytometry.Constrained linear regression was performed in Stata using least-squaresfit with individual drug treatments as the predictor variables and thecombination signatures as the response variables. The linear regressionwas constrained such that the sum of the predictor variables had toequal one and none could be negative.

Cell Culture, shRNA Constructs

Animal Usage: All experiments involving animals were reviewed andapproved by the MIT Committee for Animal Care (CAC). BALB/c mice(female, 12-16 weeks old) were used for toxicity and pharmacokineticstudies and for therapeutic efficacy study while receiving analfalfa-free diet (TestDiet) to minimize auto-fluorescence. Forstatistical significance, all experiments were performed on groups ofn=4+. Exclusion criteria included human error in BASP nanoparticleadministration.

In Vivo Toxicity and Pharmacokinetics:

BASP nanoparticle solutions ranging from 1.0-6.0 mg/200 μL in 5% glucosesolution/sterile pH 7.4 PBS buffer were prepared, passed through asterile 0.2 m filter (Nalgene, PES membrane), and administered intoBALB/c mice (n=4) via tail vein injection using a catheter. Adversephysical effects and weight loss were monitored, yielding an optimizeddosage of 5.0 mg/200 μL. For pharmacokinetic study, BASP nanoparticledoses (4.5 mg/200 μL) were injected into BALB/c mice (3.0 groups ofn=3), and blood samples were taken at 0, 0.25, 5, 24, and 48 h via cheekbleed. Samples were centrifuged to obtain blood serum, which were thensubjected to fluorescence imaging (IVIS, Cy5.5 λ_(ex)/λ_(em)=640/700 nm,Xenogen). Additionally, tumor localization was monitored at 3 and 24 h,followed by euthanizing the mice and subjecting the excised organs tofluorescence imaging.

In Vivo Therapeutic Efficacy:

Ovarian cancer cells (SKOV-3; ATCC) were grown in RPMI-1640 mediasupplemented with 0.01 mg/mL bovine insulin, 20% fetal bovine serum in5% CO₂ humidified atmosphere (37° C.) to a final concentration of 20%;cells were then harvested, mixed with Matrigel and sterile pH 7.4 PBSbuffer, filtered through sterile 0.2 μm filters, and subcutaneouslyinjected on the flanks of the mice. Tumor growth was monitored until 0.9cm in cumulative diameter was reached. At this point, drug-loaded BASPnanoparticles were injected (5.0 mg/200 μL, weekly injections) to thetreatment group (n=4) while the same amount of 5% glucose wereadministered to the control group (n=4) via tail vein injection. Tumorprogression and therapeutic efficacy were monitored via IVIS imaging,caliber and/or ImageJ measurements. At set time-points, mice were takenout of the study for blood chemistry panel analysis, tumor and/or organcollection, followed by histology/pathology analysis.

In Vivo IVIS Imaging:

In vivo imaging was performed on an IVIS Spectrum-bioluminescent andfluorescent imaging system (Xenogen) at the Koch Institute forIntegrative Cancer Research at MIT. Mice were anesthetized in isofluranechamber for 10 min prior to imaging. Fluorescence imaging was acquiredbased on the Cy5.5 component of the BASP nanoparticles(λ_(ex)/λ_(em)=675/nm, exposure time 2-10 s).

Example 1: Oxaliplatin Crosslinker (OxPtXL): Synthetic Protocol

Oxaliplatin Crosslinker (OxPtXL):

A modified procedure¹ was used in the synthesis of OxPtXL (FIG. 8).Norbonene anhydride a2 (551 mg, 1.3 mmol, 4.3 eq), and dihydroxyoxaliplatin-Pt(IV) al (129 mg, 0.3 mmol, 1.0 eq) were dissolved inanhydrous DCM (10 mL). The reaction mixture was allowed to stir under N₂at room temperature for 2 weeks. The mixture was then centrifuged uponthe addition of DCM (25 mL); the solid was collected, washed with ethylacetate (30 mL×3), and followed by centrifugation (3,000 rpm, 7 min).The pure product was collected and dried under vacuum, yielding OxPtXL(197.6 mg, 79%) as a white solid. HRMS-ESI: Calcd for C₃₀H₃₄N₄O₁₂Pt:m/z=860.1712 [M+Na]⁺; Found: 860.1713 [M+Na]⁺. ¹H NMR (400 MHz, DMSO-d₆,ppm) δ_(H) 8.28 (d, J=8.7 Hz, 2H), 7.78 (t, J=11.2 Hz, 2H), 6.31 (s,4H), 4.17 (s, 4H), 3.10 (s, 4H), 2.71 (s, 4H), 2.55 (br, 2H), 2.09 (d,J=11.0 Hz, 2H), 1.53 (d, J=9.5 Hz, 4H), 1.44 (br, 2H), 1.33-1.31 (d,J=9.6 Hz, 2H), 1.22-1.09 (m, 2H). ¹³C NMR (100 MHz, d₆-DMSO, ppm): δ_(C)176.9, 172.5, 163.7, 137.8, 60.6, 47.3, 44.6, 42.6, 30.7, 23.6 (FIG.11). ¹⁹⁵Pt NMR (86 MHz, d₆-DMSO, ppm): δ_(Pt) 1660.5 (FIG. 12).

Example 2: Procedure for Brush-Arm Star Polymer (BASP) Syntheses

All BASP syntheses were performed in a glovebox under a N₂ atmosphere;however, similar results are expected under ambient conditions. All ROMPreactions followed the same general procedure, which was modified frompreviously published literature^(1,5).

Chemical Structures of all Macromonomers (MMs) and Crosslinkers (XLs):

The chemical structures of macromonomers (MMs) and crosslinkers (XLs)used are shown in FIGS. 9A to 9C. The highlighted functional groups ofCPT and DOX indicate where the drug is conjugated to the MM.

General Scheme for Brush Polymerization and Crosslinking to Form BASPs:

The general scheme for the synthesis of the reported drug-loaded brush,followed by cross-linking with the bis-norbornene functionalized Pt(IV)prodrug to afford brush-arm star polymers (BASPs) is shown in FIG. 10.

Cisplatin(cisPt)-Doxorubicin(DOX)-Camptothecin(CPT) Nanoparticles:

The general scheme for the synthesis of cisPt-DOX-CPT nanoparticles isshown in FIG. 22.

CPT-Loaded BASP (NP-CPT):

To a 4 mL vial, a suspension of AcetalXL (5.70 mg, 9.80 μmol, 15.0 eq)in THF (98.0 μL, 0.1 M AcetalXL) was prepared. To a second 4 mL vialcontaining a stir bar, CPT-MM (3.56 mg, 0.91 μmol, 1.4 eq) and PEG-MM(20.00 mg, 5.63 mol, 8.6 eq) were added. To a third vial, a solution ofGrubbs 3^(rd) generation bispyridyl catalyst G3-Cat (0.02 M in THF) wasfreshly prepared. THF (33.0 μL) was then added to the MM vial, followedby the addition of the G3-Cat solution (32.7 μL, 0.65 μmol, 1.0 eq) togive the desired MM:G3-Cat ratio of 10:1, while achieving a total MMconcentration of 0.1 M, affording a yellow solution. The reactionmixture was allowed to stir for 20 min at room temperature before analiquot (˜10 μL) was taken out and quenched with 1 drop of ethyl vinylether for GPC analysis. Next, the AcetalXL suspension was added into theMM vial in three aliquots (˜5 equiv. each addition) until the desired15.0 equiv. were added, and the polymerizing mixture was allowed to stirfor 1 h at room temperature, affording a brown solution. To quench thepolymerization, a drop of ethyl vinyl ether was then added. The newlyformed nanoparticles were transferred to an 8 kD MW cutoff dialysistubing (Spectrum Laboratories) in 5 mL THF, and the solution wasdialyzed against THF (500 mL×3, solvent exchanged every 6 h). The BASPnanoparticles were stored in THF at 0° C. (FIG. 13B).

DOX-Loaded BASP (NP-DOX):

To a 4 mL vial, a suspension of AcetalXL (5.70 mg, 9.80 μmol, 15.0 eq)in THF (98.0 μL, 0.1 M AcetalXL) was prepared. To a second 4 mL vialcontaining a stir bar, DOX-MM (3.80 mg, 0.91 μmol, 1.4 eq) and PEG-MM(20.00 mg, 5.63 μmol, 8.6 eq) were added. To a third vial, a solution ofGrubbs 3^(rd) generation bispyridyl catalyst G3-Cat (0.02 M in THF) wasfreshly prepared. THF (33.0 μL) was then added to the MM vial, followedby the addition of the G3-Cat solution (32.7 μL, 0.65 μmol, 1.0 eq) togive the desired MM:G3-Cat ratio of 10:1, while achieving a total MMconcentration of 0.1M, affording a red solution. The reaction mixturewas allowed to stir for 20 min at room temperature before an aliquot(˜10 μL) was taken out and quenched with 1 drop of ethyl vinyl ether forGPC analysis. The AcetalXL suspension was then added into the MM vial inthree aliquots (5 equiv. each addition) until the desired 15.0 equiv.were added, and the polymerizing mixture was allowed to stir for 1 h atroom temperature, affording a red solution. To quench thepolymerization, a drop of ethyl vinyl ether was then added. The newlyformed nanoparticles were transferred to an 8 kD MW cutoff dialysistubing (Spectrum Laboratories) in 5 mL THF, and the solution wasdialyzed against THF (500 mL×3, solvent exchange every 6 h). The BASPnanoparticles were stored in THF at 0° C. (FIG. 13C).

OxPt-Loaded BASP (NP-OxPt): To a 4 mL vial containing a stir bar, OxPtXL(3.82 mg, 4.57 μmol, 5.0 eq) was added. To a second 4 mL vial containinga stir bar, PEG-MM (30.00 mg, 9.13 μmol, 10.0 eq) were added. To a thirdvial, a solution of Grubbs 3^(rd) generation bispyridyl catalyst G3-Cat(0.02 M in THF) was freshly prepared. THF (136.9 μL) was then added tothe MM vial, followed by the addition of the G3-Cat solution (45.6 μL,0.91 μmol, 1.0 eq) to give the desired MM:G3-Cat ratio of 10:1, whileachieving a total MM concentration of 0.05M, affording a yellowsolution. The reaction mixture was allowed to stir for 20 min at roomtemperature before an aliquot (˜10 μL) was taken out and quenched with 1drop of ethyl vinyl ether for GPC analysis. The polymerizing mixture wasthen transferred (163 μL) to the XL vial, and the solution was allowedto stir for 6 h at room temperature. To quench the polymerization, adrop of ethyl vinyl ether was then added. The newly formed nanoparticleswere transferred to an 8 kD MW cutoff dialysis tubing (SpectrumLaboratories) in 5 mL THF, and the solution was dialyzed against THF(500 mL×3, solvent exchange every 6 h). The BASP nanoparticles werestored in THF at 0° C. (FIG. 13A). The DTE_(M) for the NP-OxPt BASPnanoparticles was determined to be 34±8 nM.

PEG BASP (NP-PEG):

To a 4 mL vial, a suspension of AcetalXL (23.50 mg, 40.5 tmol, 14.3 eq)in THF (405 μL, 0.1 M AcetalXL) was prepared. To a second 4 mL vialcontaining a stir bar, PEG-MM (65.00 mg, 19.80 μmol, 7.0 eq) was added.To a third vial, a solution of Grubbs 3^(rd) generation bispyridylcatalyst G3-Cat (0.02 M in THF) was freshly prepared. THF (100 μL) wasthen added to the MM vial, followed by the addition of the G3-Catsolution (98.0 μL, 2.82 μmol, 1.0 eq) to give the desired MM:G3-Catratio of 7:1, while achieving a total MM concentration of 0.1M,affording a yellow solution. The reaction mixture was allowed to stirfor 20 min at room temperature before an aliquot (˜10 μL) was taken outand quenched with 1 drop of ethyl vinyl ether for GPC analysis. TheAcetalXL suspension was then added dropwise (in 3 aliquots of ˜130 μL)over the course of 10 min into the MM vial, and the polymerizing mixturewas allowed to stir for 3 h at room temperature, affording a brownsolution. To quench the polymerization, a drop of ethyl vinyl ether wasthen added. The newly formed nanoparticles were transferred to an 8 kDMW cutoff dialysis tubing (Spectrum Laboratories) in 5 mL THF, and thesolution was dialyzed against THF (500 mL×3, solvent exchange every 6h). The BASP nanoparticles were stored in THF at 0° C. (FIG. 13D).

CPT-DOX-CisPt BASP (NP-3D-CisPt):

To a 4 mL vial containing a stir bar, CisPtXL (0.82 mg, 1.12 μmol, 3.0eq) was added. To a second 4 mL vial containing a stir bar, CPT-MM (3.01mg, 0.77 μmol, 2.1 eq), DOX-MM (1.27 mg, 0.31 μmol, 0.8 eq), and PEG-MM(5.00 mg, 1.52 μmol, 4.1 eq) were added. To a third vial, a solution ofGrubbs 3^(rd) generation bispyridyl catalyst G3-Cat (0.02 M in THF) wasfreshly prepared. THF (33.4 μL) was then added to the MM vial, followedby the addition of the G3-Cat solution (18.6 μL, 0.37 μmol, 1.0 eq) togive the desired MM:G3-Cat ratio of 7:1, while achieving a total MMconcentration of 0.05M, affording a red solution. The reaction mixturewas allowed to stir for 20 min at room temperature before an aliquot(˜10 μL) was taken out and quenched with 1 drop of ethyl vinyl ether forGPC analysis. The polymerizing mixture was then transferred to the XLvial, and the solution was allowed to stir for 6 h at room temperature.To quench the polymerization, a drop of ethyl vinyl ether was thenadded. The newly formed nanoparticles were transferred to an 8 kD MWcutoff dialysis tubing (Spectrum Laboratories) in 5 mL THF, and thesolution was dialyzed against THF (500 mL×3, solvent exchange every 6h). The BASP nanoparticles were stored in THF at 0° C.

CPT-DOX-PC-OxPt BASP (NP-3D-PC-OxPt):

To a 4 mL vial containing a stir bar, OxPtXL (7.42 mg, 8.86 μmol, 5.0eq) was added. To a second 4 mL vial containing a stir bar, CPT-MM(24.00 mg, 6.13 μmol, 3.5 eq), DOX-PC-MM (10.27 mg, 2.46 μmol, 1.4 eq),and PEG-MM (30.00 mg, 9.13 μmol, 5.2 eq) were added. To a third vial, asolution of Grubbs 3^(rd) generation bispyridyl catalyst G3-Cat (0.02 Min THF) was freshly prepared. THF (266 μL) was then added to the MMvial, followed by the addition of the G3-Cat solution (88.4 μL, 1.77μmol, 1.0 eq) to give the desired MM:G3-Cat ratio of 10:1, whileachieving a total MM concentration of 0.05M, affording a red solution.The reaction mixture was allowed to stir for 20 min at room temperaturebefore an aliquot (˜10 μL) was taken out and quenched with 1 drop ofethyl vinyl ether for GPC analysis. The polymerizing mixture was thentransferred (334 μL) to the XL vial, and the solution was allowed tostir for 6 h at room temperature. To quench the polymerization, a dropof ethyl vinyl ether was then added. The newly formed nanoparticles weretransferred to an 8 kD MW cutoff dialysis tubing (Spectrum Laboratories)in 5 mL THF, and the solution was dialyzed against THF (500 mL×3,solvent exchange every 6 h). The BASP nanoparticles were stored in THFat 0° C. The D_(H) for the NP-3D-PC-OxPt BASP nanoparticles wasdetermined to be 16±3 nM.

CPT-Diluted DOX-PC-OxPt BASP (NP-3D-DD-OxPt):

To a 4 mL vial containing a stir bar, OxPtXL (7.66 mg, 9.14 μmol, 5.0eq) was added. To a second 4 mL vial containing a stir bar, CPT-MM(35.77 mg, 9.14 μmol, 5.0 eq), DOX-PC-MM (0.0763 mg, 0.0183 μmol, 0.01eq), and PEG-MM (30.00 mg, 9.13 μmol, 4.99 eq) were added. To a thirdvial, a solution of Grubbs 3^(rd) generation bispyridyl catalyst G3-Cat(0.02 M in THF) was freshly prepared. THF (274 μL) was then added to theMM vial, followed by the addition of the G3-Cat solution (91.9 μL, 1.83μmol, 1.0 eq) to give the desired MM:G3-Cat ratio of 10:1, whileachieving a total MM concentration of 0.05M, affording a yellowsolution. The reaction mixture was allowed to stir for 20 min at roomtemperature before an aliquot (˜10 μL) was taken out and quenched with 1drop of ethyl vinyl ether for GPC analysis. The polymerizing mixture wasthen transferred (346 L) to the XL vial, and the solution was allowed tostir for 6 h at room temperature. To quench the polymerization, a dropof ethyl vinyl ether was then added. The newly formed nanoparticles weretransferred to an 8 kD MW cutoff dialysis tubing (Spectrum Laboratories)in 5 mL THF, and the solution was dialyzed against THF (500 mL×3,solvent exchange every 6 h). The BASP nanoparticles were stored in THFat 0° C. The D_(TEM) for the NP-3D-DD-OxPt BASP nanoparticles wasdetermined to be 57±33 nM and the D_(H) was determined to be 37±21 nM.

CPT-DOX-OxPt BASP (NP-3D-OxPt):

To a 4 mL vial containing a stir bar, OxPtXL (7.63 mg, 9.11 μmol, 5.0eq) was added. To a second 4 mL vial containing a stir bar, CPT-MM(24.66 mg, 6.30 μmol, 3.5 eq), DOX-MM (10.59 mg, 2.53 μmol, 1.4 eq), andPEG-MM (30.00 mg, 9.38 μmol, 5.2 eq) were added. To a third vial, asolution of Grubbs 3^(rd) generation bispyridyl catalyst G3-Cat (0.02 Min THF) was freshly prepared. THF (273 μL) was then added to the MMvial, followed by the addition of the G3-Cat solution (91.0 μL, 1.82μmol, 1.0 eq) to give the desired MM:G3-Cat ratio of 10:1, whileachieving a total MM concentration of 0.05M, affording a red solution.The reaction mixture was allowed to stir for 20 min at room temperaturebefore an aliquot (˜10 μL) was taken out and quenched with 1 drop ofethyl vinyl ether for GPC analysis. The polymerizing mixture was thentransferred (344 μL) to the XL vial, and the solution was allowed tostir for 6 h at room temperature. To quench the polymerization, a dropof ethyl vinyl ether was then added. The newly formed nanoparticles weretransferred to an 8 kD MW cutoff dialysis tubing (Spectrum Laboratories)in 5 mL THF, and the solution was dialyzed against THF (500 mL×3,solvent exchange every 6 h). The BASP nanoparticles were stored in THFat 0° C. (FIGS. 23C to 23D).

CPT-DOX-OxPt-Cy5.5 BASP (NP-3D-OxPt-Cy5.5):

To a 4 mL vial containing a stir bar, OxPtXL (7.82 mg, 9.34 μmol, 5.0eq) was added. To a second 4 mL vial containing a stir bar, CPT-MM(25.30 mg, 6.46 μmol, 3.5 eq), DOX-MM (10.86 mg, 2.60 μmol, 1.4 eq),Cy5.5-MM (1.00 mg, 0.25 μmol, 0.13 eq), and PEG-MM (30.00 mg, 9.38 μmol,5.0 eq) were added. To a third vial, a solution of Grubbs 3^(rd)generation bispyridyl catalyst G3-Cat (0.02 M in THF) was freshlyprepared. THF (275 μL) was then added to the MM vial, followed by theaddition of the G3-Cat solution (93.4 μL, 1.87 μmol, 1.0 eq) to give thedesired MM:G3-Cat ratio of 10:1, while achieving a total MMconcentration of 0.05M, affording a dark brown solution. The reactionmixture was allowed to stir for 20 min at room temperature before analiquot (˜10 μL) was taken out and quenched with 1 drop of ethyl vinylether for GPC analysis. The polymerizing mixture was then transferred tothe XL vial, and the solution was allowed to stir for 6 h at roomtemperature. To quench the polymerization, a drop of ethyl vinyl etherwas then added. The newly formed nanoparticles were transferred to an 8kD MW cutoff dialysis tubing (Spectrum Laboratories) in 5 mL THF, andthe solution was dialyzed against THF (500 mL×3, solvent exchange every6 h). The BASP nanoparticles were stored in THF at 0° C. (FIGS. 23A to23B).

Free Drug Combination (DOX-CPT-OxPt): A stock solution of free DOX andCPT at 0.50 mg/mL (DOX) and 0.79 mg/mL (CPT) in 5% glucose was prepared.To a second vial, a free OxPt stock solution (24.75 mg/mL) in DMSO wasprepared. The OxPt solution was diluted 20-fold with the DOX-CPTsolution, forming the final free drug solution with 0.47 mg/mL DOX, 0.75mg/mL CPT, and 1.24 mg/mL OxPt. The final solution contained 5% DMSO;the net amount and composition of drug delivered was matched to the BASPsystem at 200 μL injections.

General Scheme for Iterative Exponential Growth+Analysis:

A general scheme analysis for the IEG+ is shown in FIG. 27.

Analysis of Homopolymer Blocks:

A general synthesis of homopolymer blocks was performed, resulting in a32-unit polymer (FIG. 28A). Analysis was then performed using MALDI(FIG. 28B), gel permeation chromatography (GPC) (FIG. 28C), and ¹H NMR(FIG. 28D).

Analysis of Alternating Copolymer Blocks:

A general synthesis of alternating copolymer blocks was performed withfurther analysis done using MALDI and GPC (FIG. 29).

Example 3: RNAi Signature Assay

Heat Map and Principle Component Analysis of UV-Stimulated and DilutedDOX NPs: A signature assay heat map (FIG. 14A) illustrating the effectthat UV-triggered release of DOX has on the mechanism of action of thethree-drug-loaded nanoparticle is shown. The principal components werefurther analyzed using a principal component analysis (FIG. 14B).

RNAi Signatures and Classification of Individual Free Drugs, Prodrugs,and Nanoparticles:

Eμ-Myc p19_(Arf−/−) lymphoma cells were infected at about 30% withGFP-tagged shRNAs. The cells were then treated with drug to kill 80-90%of cells as judged by propidium iodide exclusion via flow cytometry at48 h. At 72 h GFP positivity was assessed via flow cytometry. Using theRNAi signature approach, the free drug, prodrug, single-drug-conjugatedBASPs, and multi-drug conjugated BASPs illustrated in FIGS. 9A-9C werecharacterized. The signature assay of native DOX and prodrugs DOX-MM andNP-DOX classified (FIG. 20A) each species as a Topoisomerase II (Top2)poison. Furthermore, CPT, CPT-MM, and NP-CPT were all classified (FIG.20B) as Topoisomerase I (Top1) poisons. Unexpectedly, the prodrugsCisPtXL and NP-CisPt were classified (FIG. 20C) as new categories notrepresented in the reference set, and not as DNA cross-linkers, theanticipated mechanism of action of free cisplatin. This observationindicates that prodrugs and/or NPs are capable of altering a drug'sexpected mechanism of action. In contrast, the free drug OxPt (a CisPtderivative comprised of bidentate ligands), OxPtXL, and the NP-OxPtclassified similarly (FIG. 20D), namely as transcription/translationinhibitors. Hence, the deviation of CisPtXL and NP-CisPt from the knownfree drug mechanism of action is not an occurrence common to allPt(IV)-based chemotherapeutic prodrugs investigated with the RNAisignature assay. Next, the RNAi signatures for each of the free drugsand their corresponding prodrug monomers and BASPs were plotted (FIG.20E) using principal component analysis (PCA). PCA is a means ofrepresenting the variance in a multi-dimensional dataset in fewerdimensions. This plot indicates that the CisPtXL and NP-CisPt are bothmore similar to the transcription/translation inhibitors than to the DNAcross-linkers. One hypothesis that may explain the observed differencebetween the cisplatin and oxaliplatin prodrug mechanisms is related tothe ligand lability of these species. Inside the cell, where theconcentration of chloride ions is much lower than in the extracellularmilieu (2 to 30 mM for the former compared to ˜100 mM for the latter),the weakly bound chloride ligands of free cisplatin are replaced withaquo ligands. This diaquo species induces cytotoxic inter- orintra-strand DNA cross-links. In the case of the cisplatin prodrugsdisclosed herein, it is possible that the axial norbornene-carboxylateligand that is released upon intracellular reduction re-binds to anequatorial position of the platinum center, thus, forming acarboxylate-Pt(II) complex rather than the expected diaquo complex. Thisaltered ligand composition could then generate monofunctional DNAadducts as opposed to completely cross-linked ones. In the case ofOxPtXL prodrug, the bidentate carboxylate ligands may be able toout-compete the norbornene-based carboxylates that result from thereduction of the Pt(IV) prodrug. Therefore, no changes in the mechanismof action of OxPtXL or NP-OxPt would be observed using the RNAisignature assay. This hypothesis is supported by a comparison of thecorresponding Pt(II) release profiles (FIG. 15) associated with each NPin the presence of GSH. The release of platinum from NP-OxPt plateaus atapproximately 75 days, whereas release of platinum from NP-CisPt neverplateaus within the scope of a 270 day investigation, thus, suggestingthat platinum remains bound to the polymeric carrier. Additionally,utilizing a CisPt-DNA adduct specific antibody, the genomic DNA isolatedfrom murine lymphoma cells after 8 h of drug treatment was analyzed. Itwas observed that Cisplatin-DNA adducts are only detected (FIG. 13A-D)as a result of CisPt treatment, and not CisPtXL, further confirming thelack of expected bifunctional adduct formation from CisPtXL. As anadditional functional validation of the RNAi signature results, DOX andCPT free drug, as well as NP-DOX and NP-CPT, were also tested withvalidated Top1 and Top2A shRNAs via a GFP competition assay. Knockdownof Top1 elicited resistance to the Top1 poison CPT and sensitivity tothe Top2 poison DOX. The inverse was true for knockdown of Top2A: cellsharboring the Top2A shRNA were resistant to free DOX and exhibitedsensitivity to free CPT. These results were recapitulated for therespective BASPs, specifically NP-CPT and NP-DOX, where each BASPproduced (FIG. 20F) similar RNAi signatures as their corresponding freedrugs CPT and DOX, respectively.

Contribution of Different Drugs to Mechanism of Action of CombinationNanoparticles as Predicted by Constrained Linear Regression:

Constrained linear regression was performed in Matlab 2015a using the‘lsqlin’ function with individual drug treatments as the predictorvariables and the combination signatures as the response variables. Thelinear regression was constrained such that the sum of the predictorvariables had to equal one and none could be negative. This was repeatedfor all combinations of replicates for both the response and predictorvariables. This resulted in a minimum of 120 individual linearregressions. The results of all regressions were then averaged to obtainthe final result. Error is the standard error of the mean of all of theregressions. In order to use RNAi-based signatures to determine therelative effective contribution of multiple drugs within a single NP, aBASP capable of externally triggered drug release was designed to easilyvalidate the presence or absence of the triggered drug in a combinationof other drugs without having to change the BASP composition. For this,CPT-MM and photocleavable DOX-PC-MM were crosslinked with OxPtXL viaBF-ROMP to yield 3-drug-conjugated BASP NP-3D-PC-OxPt. The incorporationof the UV-triggered DOX-PC-MM allows for rapid release of free DOX uponexposure to 365 nm light. NP-3D-PC-OxPt was used to treat cells eitherwith or without light irradiation and RNAi signatures were obtained.Constrained linear regression was then performed (FIGS. 14-A and 21A) onthe RNAi signatures to ascertain the relative effective contributions ofeach drug's mechanism of action between the UV-irradiated andnon-irradiated BASP treatments. As anticipated, the signatures obtainedin the absence of light irradiation showed (FIG. 21A, ‘no UV’) that freeDOX was not predicted to have contributed to the mechanism of action ofthe NP, as determined by constrained linear regression. Conversely,constrained linear regression predicted (FIG. 21A, ‘UV’) that free DOXcontributed to the UV-irradiated NP mechanism of action at approximately55%. Then, the mechanism of action of two novel BASPs were analyzed thateither contained DOX-PC-MM diluted to ˜0.2% of the amount used inNP-3D-PC-OxPt (NP-3D-DD-OxPt, where DD=Diluted DOX), or possessed thenon-photo-cleavable DOX-MM (NP-3D-OxPt). In both of these cases,regardless of treatment with UV light, constrained linear regression wasable to identify (FIGS. 14A-B and 21B-C) the contribution of free DOX tothe combined mechanism of action.

Example 4: Histology

Comparison of H&E Stained Liver Cross Sections of Treated and UntreatedMice:

Different views of paraffin-embedded and H&E stained liver crosssections were obtained from control mice (FIG. 15, top panel),nanoparticle-treated mice starting with tumors possessing 1 cm and 0.5cm diameters (FIG. 15, middle panel), and free drug treated mice (FIG.15, bottom panel).

Comparison of H&E Stained Tumor Cross Sections of Treated and UntreatedMice:

Different views of paraffin-embedded and H&E stained left (L) and right(R) tumor cross sections were obtained from control mice (FIG. 16, toppanel), nanoparticle-treated mice starting with tumors possessing 1 cmand 0.5 cm diameters (FIG. 16, middle panel), and free drug treated mice(FIG. 16, bottom panel).

Comparison of H&E Stained Tumor and Liver Cross Sections of Treated andUntreated Mice:

Different views of H&E stained left (L) and right (R) tumor crosssections obtained from a control mouse (FIG. 26, top panel), H&E stainedliver cross sections obtained from acute and chronic mice (FIG. 26,middle panel), and H&E stained right (R) tumor cross sections obtainedfrom acute and chronic mice (FIG. 26, bottom panel).

Example 5: Blood Chemistry Analysis

Pharmacokinetics of OxPt-Loaded BASP (NP-OxPt): Pharmacokinetics over a126 h period associated with NP-OxPt containing 1% Cy5.5-MM injected(4.5 mg/dose; 18 mg/kg) in BALB/c mice are shown in FIG. 17A. Tumorlocalization in NCR-NU mice injected with NP-OxPt containing 1% Cy5.5-MMis shown in FIG. 17B.

Blood Panel Analysis of Nanoparticle/Free-Drug Treated and ControlNCR-NU Mice:

Blood panel analysis of biomarkers associated with NCR-NU mice treatedwith: i) NP-3D-OxPt (#114 bars: Chronic; #19 bars: Acute); ii) the freedrug combination (#5 bars: DOX-CPT-OxPt); and iii) 5% glucose solutionsis shown in FIG. 18. B/C=BUN/Creatinine.

Example 6: In Vivo Efficacy

Animal Usage:

All experiments involving animals were reviewed and approved by the MITCommittee for Animal Care (CAC). BALB/c mice (female, 8-12 weeks old,Taconic) were used for toxicity and pharmacokinetic studies. NCR-NU nudemice (female, 8-12 weeks old, Taconic) were used for biodistribution andtherapeutic efficacy studies while receiving an alfalfa-free diet(TestDiet) to minimize auto-fluorescence. For statistical significance,all experiments were performed on groups of n=4+.

Tumor Volume Plot, Survival Curve, and Nanoparticle Localization in 1 cmDiameter Tumor Study:

Ovarian cancer cells (SKOV-3; ATCC) were grown in RPMI-1640 mediasupplemented with 0.01 mg/mL bovine insulin, 20% fetal bovine serum in5% CO₂ humidified atmosphere (37° C.) to a final concentration of 20%.The cells were then harvested, mixed with Matrigel and sterile pH 7.4PBS buffer (1:1), filtered through sterile 0.2 μm filters, and injectedsubcutaneously (1.25×106 cells) in the hind flanks of the mice. Tumorgrowth was monitored for 2-4 wks until either 0.5 or 1.0 cm incumulative diameter was reached as the starting point for the twoefficacy studies, after which treatment groups were randomized. At thispoint, three-drug-loaded BASP nanoparticles (NP-3D-OxPt) were injected(5.0 mg/200 μL, approx. weekly injections) to the treatment group(n=4+), while the same volume of 5% glucose was administered to thecontrol group (n=4+) via tail vein injection. Tumor progression andtherapeutic efficacy were monitored via caliper and ImageJ measurements.At set time-points, mice were removed from the study for blood chemistrypanel analysis (Charles River), tumor and/or organ excision, followed byhistology and pathology analysis. Non-sacrificial mice were removed fromthe study if one or more of the following criteria were met: i) bodyweight decreased by 10% or more compared to the body weight at the startof the study, ii) the diameter of the tumor doubled compared to thestarting diameter (i.e., if starting with 0.5 cm diameter, then themouse was removed at 1.0 cm; or if starting at 1.0 cm, then the mousewas removed at 2.0 cm in diameter), or iii) development of necrotic,and/or cracked and bleeding tumor tissue. As discussed above, tumorlocalization of NP-3D-OxPt-Cy5.5 was investigated by injecting NCR-NUmice with 5 mg of the three-drug-loaded nanoparticle and monitoring(excitation at 675 nm; emission at 720 nm) the epifluorescence at 3 and20 h in an IVIS whole animal imaging system (FIG. 19A). Tumor volumeplot and treatment schedule for the in vivo efficacy study of micepossessing 1 cm in diameter subcutaneous xenograft tumors are shown inFIG. 19B. FIG. 19C shows the survival curve illustrating the survivalprobability of the nanoparticle treated mice versus the control micethat were only injected with 5% glucose solutions.

Tumor Volume Plot, Survival Curve, and Nanoparticle Localization in 0.5cm Diameter Tumor Study:

To investigate the therapeutic efficacy of the three-drug-loadedNP-3D-OxPt in vivo, NCR-NU mice were injected subcutaneously in eachhind flank with 1.25×106 ovarian carcinoma cells (SKOV-3, ATCC) mixed(1:1) with Matrigel and PBS buffer. Tumor growth was monitored for 2-4wks until the tumor reached approximately 0.5 cm in diameter, at whichpoint three treatment groups were established: those treated withsterile-filtered 5% aqueous glucose solutions containing either i)NP-3D-OxPt, ii) a free drug formulation at the same DOX, CPT, and OxPtconcentrations as NP-3D-OxPt, or iii) the blank vehicle. The BASPtreatment schedule consisted of four tail-vein injections over 22 days(˜1 inj./wk), where each injection per mouse comprised of 5 mg BASP in200 μL of 5% glucose solution, a dose that is close to the maximumsolubility limit (˜6 mg/200 μL) of the three-drug-conjugated BASP. Since˜10% of each NP-3D-OxPt is made up of the three anti-cancer drugs, eachdose is equal to ˜20 mg total drug/kg mouse. Although the ratio of drugloading in NP-3D-OxPt should afford maximum tolerable doses (MTD) thatmatch those of free DOX and CPT, and more than twice that of OxPt, theresults from the RNAi signature assay suggest that, at least in vitro,the effective contribution from all three drugs toward the overallmechanism of action should be nearly equal. Simultaneous delivery of allthree drugs within one BASP entity ensures that the three drugs willarrive at the tumor in a ratio defined by the BASP, which precludesdifferences in pharmacokinetics and biodistribution that could beobserved for mixtures of single-drug-conjugated NPs. Thus, resultsobtained at the cell culture level can be expected to translate to thetumor. As a consequence of the branched MM design, the BASP possesses aprotective PEG outer layer, a feature that greatly enhances itsbioavailability and leads to a blood circulation half-life (t_(1/2)) of43±8 h for NP-OxPt in NCR-NU mice (FIG. 14A-B). This increasedcirculation in the bloodstream allows sufficient time for passiveaccumulation of the BASPs in tumors (FIGS. 14A-B, 19A-B, and 24A), aprocess which occurs within 20-24 h post-injection by way of theenhanced permeability and retention (EPR) effect. A qualitativebiodistribution analysis of NP-OxPt loaded with 1% Cy5.5-MM fluorophorereveals (FIG. 15) tumor and liver accumulation after 24 h, followed byexcretion of the residual NP in the mouse feces after 48 h. The micetreated with the free drug formulation lost significant total body massafter only two treatments (FIG. 24D) and therefore had to be euthanized,with their blood serum and tissues harvested for post-therapeuticanalysis. The BASP treatment group, however, displayed (FIG. 24D)excellent therapeutic tolerance, as evidenced by a consistent total bodymass and no noticeable adverse effects throughout the course of thestudy. The tumor volume progression plot illustrates (FIG. 24B) a clearregression in tumor growth associated with the BASP treatment group,whereas the mice in the vehicle control group showed no signs of tumorregression. After the fourth and final BASP treatment, both the BASPtreatment and the vehicle groups showed a continued increase of tumorvolumes though the tumors in the former case grew at a slower rate. Thesurvival rate of each treatment group reflects (FIG. 24C) the overalltherapeutic tolerance and efficacy associated with the BASP combinationtherapy, whereas the mice from the vehicle control group were removed asdeemed necessary, according to the criteria established in our Committeeon Animal Care protocol. After completion of the 60-day therapeuticefficacy study, the surviving mice from the BASP treatment group weresacrificed and their blood serum and organs were harvested in order toperform a blood panel analysis (FIG. 17B). This allowed for comparisonof toxicity between the post-study chronically treated mice, themid-study acutely treated mice, and vehicle mice. As anticipated, theacutely and chronically treated mice associated with the BASP treatmentgroup demonstrated little to no kidney damage as evidenced by the lowblood urea nitrogen to creatinine ratio, as well as very low amounts ofliver damage-related biomarkers, such as alanine and aspartateaminotransferases (FIG. 17B). Pathology of the paraffin-embedded,H&E-stained cross-sections (˜5 m thick) of the livers (FIG. 18) from theBASP-treated and vehicle mice supports this biomarker quantificationanalysis. Cross-sections of the paraffin-embedded, H&E-stained tumorsharvested from acute/chronic BASP-treated mice show (FIGS. 19A-C) strongevidence of cancer cell death in direct contrast to the healthy vehiclecontrol tumor tissue. To assess the degree to which our NP-3D-OxPt dosecould demonstrate efficacy in larger tumors from the same cancer cellline, we carried out another in vivo therapeutic efficacy study starting(FIGS. 19A-C) with tumors ˜1.0 cm in diameter and observed comparabletherapeutic tolerance and efficacy relative to the results from thefirst study.

Tumor Reduction:

Nearly complete tumor reduction was observed in Mouse #105 over a 21 daytreatment schedule and 12 week observation using CPT-DOX-OxPt (FIG. 25).

Discussion

It has been demonstrated that a modular BASP combination therapyplatform—comprised of drug-conjugated MMs and Pt(IV)-based XLs—is aneffective means of delivering a precise ratio of an otherwise toxiccombination of three drugs to a subcutaneous xenograft tumor in mice.Previously, there was no way to verify that the drug mechanism of actionwas not disrupted by incorporation into the nanoparticle. The mechanismof action associated with the reported prodrugs and single-drug-loadedBASPs was characterized using an RNAi signature assay that allows for afast and accurate in vitro combinatorial screening that is capable ofpredicting a prodrug's mechanism of action. Although the Pt(IV)-diesterXL—intended to be a precursor to CisPt—did not behave as anticipated invitro, the RNAi signatures allowed the identification of anotherPt(IV)-diester XL that functions as a faithful precursor to OxPt. Thus,a functional genetic assay was employed to ensure that the conjugateddrugs—whose mechanistic targets differ from one another—behaved asintended. Moreover, constrained linear regression analysis, paired withRNAi signatures, revealed the relative effective contributions of eachdrug towards the mechanism of action in our three-drug-conjugated BASPs.The ability to assess the in vitro contribution of each drug addsanother layer of quality control to NP-based drug delivery. The initialstoichiometric ratios can be tuned to achieve BASPs where all drugscontribute equally, or BASPs that possess disparate drug contributionsthat may potentially maximize synergistic ratios, all the while takinginto account the kinetics associated with the release of each drug fromthe combination NP platformThis modular platform and the RNAi-basedmechanism of action predictive assay can be further utilized to assessdifferent combinations of drugs in an effort to treat other types ofcancer, as well as characterize nanoparticles other than BASPsconsisting of one, two, three, or potentially more drugs.

REFERENCES

-   ¹ Liao, L.; Liu, J.; Dreaden, E. C.; Morton, S. W.; Shopsowitz, K.    E.; Hammond, P. T.; Johnson, J. A. J. Am. Chem. Soc. 2014, 136,    5896-5899.-   ² Hall, M.; Dillon, C.; Zhang, M.; Beale, P.; Cai, Z.; Lai, B.;    Stampfl, A. J.; Hambley, T. J. Biol. Inorg. Chem. 2003, 8, 726-732.-   ³ Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew.    Chem. Int. Ed. 2002, 41, 4035-4037.-   ⁴ Liu, J.; Burts, A. O.; Zhukhovitsky, A. V.; Ottaviani, M. F.;    Turro, N. J.; Johnson, J. A. J. Am. Chem. Soc. 2012, 134,    16337-16344-   ⁵ Gao, A. X.; Liao, L.; Johnson, J. A. ACS Macro Lett. 2014, 3,    854-857.-   ⁶ Sowers, M. A; McCombs, J. R.; Wang, Y.; Paletta, J. T.; Morton, S.    W.; Dreaden, E. C.; Boska, M. D.; Ottaviani, M. F.; Hammond, P. T.;    Rajca, A.; Johnson, J. A. Nature Commun. 2014, 5, 5460.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. It isalso noted that the term “including” is intended to be open and permitsthe inclusion of additional elements or steps. Where ranges are given,endpoints are included. Furthermore, unless otherwise indicated orotherwise evident from the context and understanding of one of ordinaryskill in the art, values that are expressed as ranges can assume anyspecific value or sub-range within the stated ranges in differentembodiments of the invention, to the tenth of the unit of the lowerlimit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Thoses killed in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

What is claimed is:
 1. A platinum complex of Formula (I):

or a salt thereof, wherein: each instance of R^(N1) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl, or a nitrogenprotecting group, or two R^(N1) are taken with the intervening atoms toform a heterocyclic ring; each instance of R^(N2) is independentlyhydrogen, substituted or unsubstituted C₁₋₆ alkyl, or a nitrogenprotecting group, or two R^(N2) are taken with the intervening atoms toform a heterocyclic ring; L^(N) is a linker selected from the groupconsisting of substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstituted arylene,substituted or unsubstituted heterarylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocyclylene, andcombinations thereof; and each instance of n is 1, 2, 3, 4, 5, or
 6. 2.The platinum complex of claim 1, wherein the platinum complex is ofFormula (I-a):

or a salt thereof, wherein: each instance of R^(A) is independentlyhydrogen, halogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; and each instance of R^(B) is independently hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; or two instances of R^(B) are joined to form a substitutedor unsubstituted, carbocyclic ring, or substituted or unsubstituted,heterocyclic ring.
 3. The platinum complex of claim 2, wherein theplatinum complex is of Formula (I-b):

or a salt thereof.
 4. The platinum complex of claim 2, wherein theplatinum complex is of Formula (I-c):

or a salt thereof, wherein: Ring A is a substituted or unsubstituted,monocyclic, 3- to 7-membered carbocyclic ring; each instance of R^(C) isindependently halogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, —OR^(a), —N(R^(a))₂, —SR^(a), —CN, —SCN,—C(═NR^(a))R^(a), —C(═NR^(a))OR^(a), —C(═NR^(a))N(R^(a))₂, —C(═O)R^(a),—C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂, —N(R^(a))C(═O)R^(a),—N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂, —N(R^(a))S(═O)R^(a),—N(R^(a))S(═O)OR^(a), —N(R^(a))S(═O)N(R^(a))₂, —N(R^(a))S(═O)₂R^(a),—N(R^(a))S(═O)₂OR^(a), —N(R^(a))S(═O)₂N(R^(a))₂, —OC(═O)R^(a),—OC(═O)OR^(a), or —OC(═O)N(R^(a))₂; each instance of R^(a) isindependently hydrogen, substituted or unsubstituted acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogenprotecting group when attached to a nitrogen atom, an oxygen protectinggroup when attached to an oxygen atom, or a sulfur protecting group whenattached to a sulfur atom, or two instances of R^(a) are joined to forma substituted or unsubstituted, heterocyclic ring, or substituted orunsubstituted, heteroaryl ring; and u is an integer between 0 and 8,inclusive.
 5. The platinum complex of claim 4, wherein the platinumcomplex is of Formula (I-d):

or a salt thereof.
 6. The platinum complex of claim 4, wherein theplatinum complex is of Formula (I-e):

or a salt thereof, wherein u is an integer between 0 and 8, inclusive.7. The platinum complex of claim 1, wherein the platinum complex is ofFormula (I-f):

or a salt thereof.
 8. The platinum complex of any one of claims 1-2 and4, wherein at least one instance of R^(N1) is hydrogen.
 9. The platinumcomplex of any one of claims 1-2 and 4, wherein each instance of R^(N1)is hydrogen.
 10. The platinum complex of any one of claims 1-2, 4, and8-9, wherein at least one instance of R^(N2) is hydrogen.
 11. Theplatinum complex of any one of claims 1-2, 4, and 8-9, wherein eachinstance of R^(N2) is hydrogen.
 12. The platinum complex of any one ofclaims 1 and 8-11, wherein L^(N) is substituted or unsubstitutedheterocyclylene.
 13. The platinum complex of any one of claims 1 and8-11, wherein L^(N) is substituted or unsubstituted cycloalkylene. 14.The platinum complex of any one of claims 1-13, wherein n is
 1. 15. Theplatinum complex of any one of claims 1-14, wherein each instance of

is of the formula:


16. The platinum complex of any one of claims 2-5 and 8-15, wherein atleast one instance of R^(A) is hydrogen.
 17. The platinum complex of anyone of claims 2-5 and 8-15, wherein each instance of R^(A) is hydrogen.18. The platinum complex of any one of claims 4-6 and 8-17, wherein u is0.
 19. The platinum complex of claim 1, wherein the platinum complex isof the formula:


20. The platinum complex of claim 1, wherein the platinum complex is ofthe formula:


21. A method of preparing a platinum complex of any one of claims 1-20,the method comprising the steps of: (a) oxidizing a compound of Formula(S-I):

with an oxidant to provide a compound of Formula (S-2):

(b) coupling the compound of Formula (S-2) with a compound of Formula(S-3):

to provide the platinum complex.
 22. The method of claim 21, wherein theoxidant is H₂O₂.
 23. The method of any one of claims 21-22, wherein thestep of coupling is performed in the presence of an activator.
 24. Themethod of claim 23, wherein the activator isN,N′-dicyclohexylcarbodiimide (DCC),1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI),O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphonate (HATU), or(2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (HBTU).
 25. A polymer prepared by the steps of: (a)reacting a first macromonomer of Formula (III′):

or a salt thereof, with a second macromonomer of Formula (III′), or asalt thereof, in the presence of a metathesis catalyst to provide apolymerization mixture, wherein: a is an integer from 1 to 10,inclusive; each instance of b is independently an integer from 1 to 10,inclusive; c is an integer from 1 to 200, inclusive; e is 0, 1, 2, 3, 4,5, or 6; each instance of L is independently —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, a peptide, a cleavable linker, apolymer, or a substituted or unsubstituted C₁₋₃₀ hydrocarbon chain,optionally wherein one or more carbon units of the hydrocarbon chain isindependently replaced with substituted or unsubstituted phenyl,substituted or unsubstituted triazolyl, —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C═C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance of R^(La) isindependently hydrogen, substituted or unsubstituted C₁₋₁₀ alkyl, or anitrogen protecting group, and wherein each occurrence of R^(Lb) isindependently selected from the group consisting of hydrogen, halogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl, or two R^(Lb) groups are joined to form a substituted orunsubstituted carbocyclic or substituted or unsubstituted heterocyclicring, or R^(La) and R^(Lb) are joined to form a substituted orunsubstituted heterocyclic ring; each instance of M is independentlyhydrogen or an agent; and the first macromonomer and the secondmacromonomer are the same or different from each other; and (b)contacting the polymerization mixture with a platinum complex of any oneof claims 1-20 to provide the polymer.
 26. The polymer of claim 25,wherein at least one instance of L is a substituted or unsubstitutedC₁₋₃₀ hydrocarbon chain, wherein one or more carbon units of thehydrocarbon chain is independently replaced with substituted orunsubstituted phenyl, substituted or unsubstituted triazolyl, —O—, —S—,—NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—,—C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,trans-CR^(Lb)═CR^(Lb), cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—,—C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—,—OS(═O)₂—, —S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—.
 27. The polymer of claim25, wherein at least one instance of L is a substituted or unsubstitutedC₁₋₃₀ hydrocarbon chain, wherein: one or more carbon units of thehydrocarbon chain is replaced with substituted or unsubstitutedtriazolyl; and optionally one or more carbon units of the hydrocarbonchain is independently replaced with substituted or unsubstitutedphenyl, —O—, —S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—,—C(═O)S—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—,—NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C═C—,—OC(R^(Lb))₂—, —C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—,—S(═O)₂O—, —OS(═O)₂—, —S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—.
 28. A polymerprepared by the steps of: (a) reacting a first macromonomer of Formula(III):

or a salt thereof, with a second macromonomer of Formula (III), or asalt thereof, in the presence of a metathesis catalyst to provide apolymerization mixture, wherein: a is an integer from 1 to 10,inclusive; each instance of b is independently an integer from 1 to 5,inclusive; c is an integer from 1 to 100, inclusive; e is 0, 1, 2, 3, or4; each instance of L is independently —O—, —S—, —NR^(La)—,—NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—,—OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—, trans-CR^(Lb)═CR^(Lb)—,cis-CR^(Lb)═CR^(Lb)—, —C≡C—, —OC(R^(Lb))₂—, —C(R^(Lb))₂O—,—NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—, —OS(═O)₂—,—S(═O)₂NR^(La)—, —NR^(La)S(═O)₂—, a peptide, a cleavable linker, or asubstituted or unsubstituted C₁₋₁₀ hydrocarbon chain, optionally whereinone or more carbon units of the hydrocarbon chain is replaced with —O—,—S—, —NR^(La)—, —NR^(La)C(═O)—, —C(═O)NR^(La)—, —SC(═O)—, —C(═O)S—,—OC(═O)—, —C(═O)O—, —OC(═O)O—, —OC(═O)NR^(La)—, —NR^(La)C(═O)O—,trans-CR^(Lb)═CR^(Lb)—, cis-CR^(Lb)═CR^(Lb)—, —C═C—, —OC(R^(Lb))₂—,—C(R^(Lb))₂O—, —NR^(La)C(R^(Lb))₂—, —C(R^(Lb))₂NR^(La)—, —S(═O)₂O—,—OS(═O)₂—, —S(═O)₂NR^(La)—, or —NR^(La)S(═O)₂—, wherein each instance ofR^(La) is independently hydrogen, substituted or unsubstituted C₁₋₁₀alkyl, or a nitrogen protecting group, and wherein each occurrence ofR^(Lb) is independently selected from the group consisting of hydrogen,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl, or two R^(Lb) groups are joined to form a substituted orunsubstituted carbocyclic or substituted or unsubstituted heterocyclicring, or R^(La) and R^(Lb) are joined to form a substituted orunsubstituted heterocyclic ring; each instance of M is independentlyhydrogen or a pharmaceutical agent; and the first macromonomer and thesecond macromonomer are the same or different from each other; and (b)contacting the polymerization mixture with a platinum complex of any oneof claims 1-20 to provide the polymer.
 29. The polymer of any one ofclaims 25-28, wherein the first macromonomer and the second macromonomerare the same.
 30. The polymer of any one of claims 25-28, wherein thefirst macromonomer and the second macromonomer are different from eachother.
 31. The polymer of claim 30, wherein at least one instance of Mof the first macromonomer and at least one instance of M of the secondmacromonomer are different from each other.
 32. The polymer of any oneof claims 25-31, wherein: the molar ratio of the first macromonomer tothe metathesis catalyst is between 1:1 to 20:1, inclusive; the molarratio of the second macromonomer to the metathesis catalyst is between1:1 to 20:1, inclusive; and the molar ratio of the platinum complex tothe metathesis catalyst is between 1:1 to 20:1, inclusive.
 33. Thepolymer of any one of claims 25-32, wherein the metathesis catalyst is aruthenium metathesis catalyst.
 34. The polymer of claim 33, wherein themetathesis catalyst is of the formula:


35. The polymer of any one of claims 25-34, wherein e is
 1. 36. Thepolymer of any one of claims 25-35, wherein c is an integer from 30 to100, inclusive.
 37. The polymer of any one of claims 25 and 28-36,wherein at least one instance of L is a peptide.
 38. The polymer of anyone of claims 25 and 28-36, wherein at least one instance of L is acleavable linker.
 39. The polymer of claim 38, wherein at least oneinstance of L is a photocleavable linker, a linker cleavable byreduction, or a linker cleavable by hydrolysis.
 40. The polymer of anyone of claims 25, 28-36, 38, and 39, wherein at least one instance of Lis of the formula:

wherein: each instance of the carbon atom labeled with “*” is attachedto M; each instance of R^(E) is independently halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR^(a), —N(R^(a))₂,—SR^(a), —CN, —SCN, —C(═NR^(a))R^(a), —C(═NR^(a))OR^(a),—C(═NR^(a))N(R^(a))₂, —C(═O)R^(a), —C(═O)OR^(a), —C(═O)N(R^(a))₂, —NO₂,—N(R^(a))C(═O)R^(a), —N(R^(a))C(═O)OR^(a), —N(R^(a))C(═O)N(R^(a))₂,—N(R^(a))S(═O)R^(a), —N(R^(a))S(═O)OR^(a), —N(R^(a))S(═O)N(R^(a))₂,—N(R^(a))S(═O)₂R^(a), —N(R^(a))S(═O)₂OR^(a), —N(R^(a))S(═O)₂N(R^(a))₂,—OC(═O)R^(a), —OC(═O)OR^(a), or —OC(═O)N(R^(a))₂; each instance of R^(a)is independently hydrogen, substituted or unsubstituted acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, a nitrogen protecting group when attached to a nitrogenatom, an oxygen protecting group when attached to an oxygen atom, or asulfur protecting group when attached to a sulfur atom, or two instancesof R^(a) are joined to form a substituted or unsubstituted, heterocyclicring, or substituted or unsubstituted, heteroaryl ring; each instance ofk is independently 0, 1, 2, 3, or 4; each instance of p is independentlyan integer from 1 to 10, inclusive; each instance of q is independentlyan integer from 1 to 10, inclusive; each instance of g is independentlyan integer from 1 to 10, inclusive; and each instance of h isindependently an integer from 1 to 10, inclusive.
 41. The polymer of anyone of claims 25, 28-34, and 36, wherein the macromonomer is of Formula(III-e):


42. The polymer of any one of claims 25, 28-34, and 36, wherein themacromonomer is of Formula (III-f):


43. The polymer of any one of claims 25, 28-34, and 36, wherein themacromonomer is of Formula (III-g):


44. The polymer of any one of claims 25, 28-34, and 36, wherein themacromonomer is of Formula (III-h):


45. The polymer of any one of claims 25-44, wherein at least oneinstance of M is a pharmaceutical agent.
 46. The polymer of claim 45,wherein at least one instance of M is an anti-proliferative agent. 47.The polymer of claim 46, wherein at least one instance of M is ananti-cancer agent.
 48. The polymer of claim 46, wherein at least oneinstance of M is of the formula:


49. A pharmaceutical composition comprising a polymer of any one ofclaims 25-48 and optionally a pharmaceutically acceptable excipient. 50.A kit comprising: a polymer of any one of claims 25-48 or apharmaceutical composition of claim 49; and instructions for use thepolymer or pharmaceutical composition.
 51. A method of treating aproliferative disease in a subject in need thereof comprisingadministering to the subject an effective amount of a polymer of any oneof claims 25-48 or a pharmaceutical composition of claim
 49. 52. Themethod of claim 51, wherein at least one instance of M is a therapeuticagent or prophylactic agent.
 53. The method of claim 51 or 52, whereinthe proliferative disease is cancer.
 54. The method of claim 53, whereinthe cancer is lung cancer, head-and-neck cancer, esophagus cancer,stomach cancer, breast cancer, pancreas cancer, colorectal cancer, livercancer, kidney cancer, prostate caner, glioblastomas, metastaticmelanomas, peritoneal or pleural mesotheliomas.
 55. A method ofdelivering a pharmaceutical agent to a subject comprising administeringto the subject a polymer of any one of claims 25-48 or a pharmaceuticalcomposition of claim
 49. 56. The method of any one of claims 51-55,wherein the subject is a human.
 57. A method of delivering apharmaceutical agent to a biological sample, tissue, or cell, the methodcomprising contacting the biological sample, tissue, or cell with apolymer of any one of claims 25-48 or a pharmaceutical composition ofclaim
 49. 58. The method of any one of claims 55-57, wherein thepharmaceutical agent is an anti-cancer agent.